AU2002366278A1 - Cis-2,4,5- triphenyl-imidazolines and their use in the treatment of tumors - Google Patents
Cis-2,4,5- triphenyl-imidazolines and their use in the treatment of tumors Download PDFInfo
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Abstract
The present invention provides compounds according to formula I and formula II and pharmaceutically acceptable salts and esters thereof, having the designations provided herein and which inhibit the interaction of MDM2 protein with a p53-like peptide and have antiproliferative activity.
Description
WO 03/051359 PCT/EPO2/13904 CIS-2,4,5-TRIPHENYL-IMIDAZOLINES AND THEIR USE IN THE TREATMENT OF TUMORS p53 is a tumor suppresser protein that plays a central role in protection against development of cancer. It guards cellular integrity and prevents the propagation of permanently damaged clones of cells by the induction of growth arrest or apoptosis. At the molecular level, p53 is a transcription factor that can activate a panel of genes implicated in 5 the regulation of cell cycle and apoptosis. p53 is a potent cell cycle inhibitor which is tightly regulated by MDM2 at the cellular level. MDM2 and p53 form a feedback control loop. MDM2 can bind p53 and inhibit its ability to transactivate p53-regulated genes. In addition, MDM2 mediates the ubiquitin-dependent degradation of p53. p53 can activate the expression of the MDM2 gene, thus raising the cellular level of MDM2 protein. This t0 feedback control loop insures that both MDM2 and p53 are kept at a low level in normal proliferating cells. MDM2 is also a cofactor for E2F, which plays a central role in cell cycle regulation. The ratio of MDM2 to p53 (E2F) is dysregulated in many cancers. Frequently occurring molecular defects in the pl6INK4/pl9ARF locus, for instance, have been shown 15 to affect MDM2 protein degradation. Inhibition of MDM2-p53 interaction in tumor cells with wild-type p53 should lead to accumulation of p53, cell cycle arrest and/or apoptosis. MDM2 antagonists, therefore, can offer a novel approach to cancer therapy as single agents or in combination with a broad spectrum of other antitumor therapies. The feasibility of this strategy has been shown by the use of different macromolecular tools for inhibition of 20 MDM2-p53 interaction (e.g. antibodies, antisense oligonucleotides, peptides). MDM2 also binds E2F through a conserved binding region as p53 and activates E2F-dependent transcription of cyclin A, suggesting that MDM2 antagonists might have effects in p53 mutant cells. Wells et al. J. Org. Chem., 1972, 37, 2158-2161, report synthesis of imidazolines. 25 Hunter et al., Can. J. Chem., 1972, Vol. 50, pgs. 669-77, report the preparation of amarine and isoamarine compounds which had previously been studied for chemilumrninescence (McCapra et al. Photochem. and Photobiol. 1965, 4, 1111-1121). Zupanc et al. Bull. Soc. Chem. & Tech. (Yugoslavia) 1980-81, 27/28, 71-80, report the use of triaryl imidazolines as starting materials in the preparation of EDTA derivatives. EP 363 061 to Matsumoto WO 03/051359 PCT/EPO2/13904 -2 reports imidazoline derivatives useful as immunomodulators. The compounds were indicated to have low toxicity. Treatment and/or prevention of rheumatoid arthritis, multiple sclerosis, systemic lupus, erythemathodes, and rheumatic fever were implicated. WO 00/78725 to Choueiry et al. report a method for making substituted amidine 5 compounds, and indicate that imidazoline-type compounds may be useful in the treatment of diabetes or related diseases involving impaired glucose disposal. The present invention provides at least a compound of formula I
Y
1 / X, N N X2 Y R X3 I and the pharmaceutically acceptable salts and esters thereof, wherein 10 R is -C=OR1, wherein R1 is selected from C 1
-C
6 alkyl, -C=CHCOOH, -NHCH 2
CH
2 R2, N(CH 2
CH
2
OH)CH
2
CH
2 OH, -N(CH 3
)CH
2
CH
2
NCH
3 , N(CH 3
)CH
2
CH
2
N(CH
3
)CH
3 , saturated 4-, 5- and 6-membered rings, and saturated and unsaturated 5- and 6- membered rings containing at least one 15 hetero atom wherein the hetero atom is selected from S, N and O and being optionally substituted with a group selected from C 1
-C
6 alkyl, -C=O-R5, -OH,
C
1
-C
6 alkyl optionally substituted with hydroxy, C 1
-C
6 alkyl optionally substituted with -NH 2 , N- C 1
-C
6 alkyl, -SO 2
CH
3 , =0, -CH 2
C=OCH
3 , and 5 and 6-membered saturated rings containing at least one hetero atom selected 20 from S, N and O, wherein R5 is selected from H, C 1
-C
6 alkyl, -NH 2 , -N- C 1
-C
6 alkyl, C 1
-C
6 alkyl optionally substituted with hydroxy, and C 1
-C
6 alkyl optionally substituted with NH 2 , R2 is selected from -N(CH 3
)CH
3 , -NCH 2
CH
2
NH
2 , -NH 2 , morpholinyl and piperazinyl, 25 X1, X2 and X3 are independently selected from -OH, C 1
-C
2 alkyl, C 1
-C
6 alkoxy, -Cl,-Br, -F, -CH 2
OCH
3 , and -CH 2
OCH
2
CH
3 , or one of X1, X2 or X3 WO 03/051359 PCT/EP02/13904 -3 is H and the other two are independently selected from hydroxy, C 1
-C
6 alkyl,
C
1
-C
6 alkoxy, Cl, Br, F, -CF 3 , -CH 2
OCH
3 , -CH 2
OCH
2
CH
3 , -OCH 2
CH
2 R3,
-OCH
2
CF
3 , and -OR4, or one of X1, X2 or X3 is H and the other two taken together with the two carbon atoms and the bonds between them from the 5 benzene ring to which they are optionally substituted form a 5- or 6-membered saturated ring that contains at least one hetero atom selected from S, N, and O, wherein R3 is selected from -F, -OCH 3 , -N(CH 3
)CH
3 , -Cl, -Br, unsaturated 5- and 6 membered rings containing at least one hetero atom wherein the hetero atom 10 is selected from S, N and O, R4 is a 3- to 5- membered saturated ring and Y1 and Y2 are each independently selected from -Cl, -Br, -NO 2 , -C=N, and -C=CH. The present invention also provides at least one compound of formula II
Y
1
X
4 N
Y
2 NR II 15 and the pharmaceutically acceptable salts and esters thereof, wherein R is -C=OR1, R1 is selected from C 1
-C
6 alkyl, saturated 5- and 6-membered rings, saturated 5- and 6-membered rings containing at least one hetero atom wherein the hetero atom is selected from S, N and O and being optionally substituted with a group 20 selected from C 1
-C
2 alkyl, C 1
-C
3 alcohol, -N(CH 3
)CH
3 , -C=OCH 3 , and 5 and 6-membered rings containing at least one hetero atom wherein the hetero atom is selected from S, N, and O, X4 is selected from C 1
-C
2 alkyl, C 1
-C
6 alkoxy, fluoroethoxy, -Cl, -Br, -F, OCH 2 C=OOQ, -0- C1-C 6 alkyl, -OCH2-cyclopropyl, -CH 2
OCH
2 -phenyl, 25 saturated and unsaturated 5- and 6-membered rings, saturated and unsaturated 5- and 6-membered rings containing at least one hetero atom wherein the hetero atom is selected from S, N and O, wherein WO 03/051359 PCT/EP02/13904 -4 Q is selected from H, and C 1
-C
6 alkyl, Y1 and Y2 are independently selected from -Cl, -Br, -NO 2 , -C= N and -C=H, with the proviso that where Y1 and Y2 are both -Cl, and R1 is -CH 3 or phenyl, then X4 is not -Cl. 5 It is another object of the present invention to provide pharmaceutical composition containing these compounds, and the use of those compounds in the medical therapy, especially in treatment of tumor. A still further object of the present invention is to provide a process for the preparation of those compounds. 10 The present invention provides cis-imidazolines which are small molecule inhibitors of the MDM2-p53 interaction. In cell-free and cell-based assays, compounds of the present invention are shown to inhibit the interaction of MDM2 protein with a p53-like peptide with a potency that is approximately 100 fold greater than a p53-derived peptide. In cell-based assays, these compounds demonstrate mechanistic activity. Incubation of 15 cancer cells with wild-type p53 leads to accumulation of p53 protein, induction of p 53 regulated p21 gene, and cell cycle arrest in GI and G2 phase, resulting in potent antiproliferative activity against wild-type p53 cells in vitro. In contrast, these activities were not observed in cancer cells with mutant p53 at comparable compound concentrations. Therefore, the activity of MDM2 antagonists is likely linked to its 20 mechanism of action. These compounds can be potent and selective anticancer agents. Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the present invention herein. "Effective amount" means an amount that is effective to prevent, alleviate or 25 ameliorate symptoms of disease or prolong the survival of the subject being treated. "Halogen" means fluorine, chlorine, bromine or iodine. "Hetero atom" means an atom selected from N, O and S. "IC50" refers to the concentration of a particular compound required to inhibit 50% of a specific measured activity. IC50 can be measured, inter alia, as is described 30 subsequently.
WO 03/051359 PCT/EP02/13904 -5 "Alkyl" denotes a straight-chained or branched saturated aliphatic hydrocarbon. "Lower alkyl" groups denote C 1
-C
6 alkyl groups and include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 2-butyl, pentyl, hexyl, and the like. Generally, lower alkyl is preferably C 1
-C
4 alkyl, and more preferably C 1
-C
3 alkyl. 5 "Alkoxy" denotes -O-alkyl. "Lower alkoxy" denotes -0- C1-C 6 alkyl. The term "saturated 4-, 5- and 6-membered ring" for R1 preferably refers to cyclopentyl and cyclohexyl. The term "saturated and unsaturated 5- and 6-membered rings containing at least one hetero atom selected from S, N and O" for R1 preferably refers to saturated and 10 unsatzrated ring systems like morpholinyl, piperazinyl, piperadinyl, thiophenyl, isoxazolyl, furanyl and piperazinyl, more preferably piperazinyl. The term "unsaturated 5- and 6-membedred rings containing at least one hetero atom" for R3 preferably means imidazolyl. The term "3- to 5-membered saturated ring" for R4 preferably means an aliphatic 15 ring, e.g. cyclopentyl. "Pharmaceutically acceptable ester" refers to a conventionally esterified compound of formula I having a carboxyl group, which esters retain the biological effectiveness and properties of the compounds of formula I and are cleaved in vivo (in the organism) to the corresponding active carboxylic acid. 20 Information concerning esters and the use of esters for the delivery of pharmaceutical compounds is available in Design of Prodrugs. Bundgaard H ed. (Elsevier, 1985). See also, H. Ansel et. al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp. 108-109; Krogsgaard-Larsen, et. al., Textbook of Drug Design and Development (2d Ed. 1996) at pp. 152-191. 25 "Pharmaceutically acceptable salt" refers to conventional acid-addition salts or base addition salts that retain the biological effectiveness and properties of the compounds of the present invention and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, 30 sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such WO 03/051359 PCT/EP02/13904 -6 as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Sample base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethylammonium hydroxide. Chemical 5 modification of a pharmaceutical compound (i.e. drug) into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See, e.g., H. Ansel et. al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp. 196 and 1456-1457. 10 "Pharmaceutically acceptable," such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered. "Substituted," as in substituted alkyl, means that the substitution can occur at one or more positions and, unless otherwise indicated, that the substituents at each substitution 15 site are independently selected from the specified options. "Therapeutically effective amount" means an amount of at least one designated compound, that significantly inhibits proliferation and/or prevents differentiation of a human tumor cell, including human tumor cell lines. The present invention concerns compounds of formula I Y1 y 1 N \ N X2 Y R X3 20 and the pharmaceutically acceptable salts and esters thereof, wherein R is -C=OR1, wherein R1 is selected from C 1
-C
6 alkyl, -C=CHCOOH, -NHCH 2
CH
2 R2, N(CH 2
CH
2
OH)CH
2
CH
2 OH, -N(CH 3
)CH
2
CH
2
NCH
3 , - WO 03/051359 PCT/EP02/13904 -7
N(CH
3
)CH
2
CH
2
N(CH
3
)CH
3 , saturated 4-, 5- and 6-membered rings, and saturated and unsaturated 5- and 6- membered rings containing at least one hetero atom wherein the hetero atom is selected from S, N and O and being optionally substituted with a group selected from C 1
-C
6 alkyl, -C=O-R5, -OH, 5 C1-C 6 alkyl optionally substituted with hydroxy, C-C 6 alkyl optionally substituted with -NH 2 , N- C 1
-C
6 alkyl, -SO 2
CH
3 , =0, -CH 2
C=OCH
3 , and 5 and 6-membered saturated rings containing at least one hetero atom selected from S, N and O, wherein R5 is selected from H, C 1
-C
6 alkyl, -NH 2 , -N- C 1
-C
6 alkyl, C 1
-C
6 alkyl optionally 10 substituted with hydroxy, and C 1
-C
6 alkyl optionally substituted with NH 2 , R2 is selected from -N(CH 3
)CH
3 , -NCH 2
CH
2
NH
2 , -NH 2 , morpholinyl and piperazinyl, Xl, X2 and X3 are independently selected from -OH, C 1
-C
2 alkyl, C 1
-C
6 alkoxy, -Cl,-Br, -F, -CH 2
OCH
3 , and -CH 2
OCH
2
CH
3 , or one ofX1, X2 or X3 15 is H and the other two are independently selected from hydroxy, C 1
-C
6 alkyl,
C-C
6 alkoxy, Cl, Br, F, -CF 3 , -CH 2
OCH
3 , -CH 2
OCH
2
CH
3 , -OCH 2
CH
2 R3, OCH 2
CF
3 , and -OR4, or one of X1, X2 or X3 is H and the other two taken together with the two carbon atoms and the bonds between them from the benzene ring to which they are optionally substituted form a 5- or 6-membered 20 saturated ring that contains at least one hetero atom selected from S, N, and O, wherein R3 is selected from -F, -OCH 3 , -N(CH 3
)CH
3 , -Cl, -Br, unsaturated 5- and 6 membered rings containing at least one hetero atom wherein the hetero atom is selected from S, N and O, 25 R4 is a 3- to 5- membered saturated ring and Y1 and Y2 are each independently selected from -Cl, -Br, -NO 2 , -C=N, and -C=CH. In a preferred embodiment, the invention comprises compounds of formula I wherein Y1 and Y2 are each independently selected from -Cl and -Br. In another preferred embodiment, the present invention concerns compounds of 30 formula I, wherein R1 is selected from morpholinyl, piperazinyl, piperadinyl, cyclopentyl, cyclohexyl, thiophenyl, isoxazolyl, and furanyl,piperazinyl substituted with at least one group selected from C 1
-C
3 alkyl, -C 1
-C
2 alkoxy, -C=OCH 3 , -SO 2
CH
3 , -C=O, -OH, WO 03/051359 PCT/EPO2/13904 -8
-CH
2
NH
2 , -C=OCH 2
NH
2 , -C=OCH 2 OH, -C=OC(OH)CH 2
OH,-CH
2
C(OH)-CH
2 OH,
-C=ON(CH
2
-)
2 , -C=ONH 2 , and -C=ON(CH 3
)CH
3
,-C=OCH(CH
3 ) 2, -CH 2
C=OCH
3 ,
-CH
2
CH(OH)CH
3 , -CH(CH 3
)CH(OH)CH
3 and -CH 2
CH
2 OH. In a further preferred embodiment, the present invention concerns compounds of 5 formula I, wherein one of X1, X2 and X3 is H and the other two are independently selected from hydroxy, C 1
-C
s alkoxy, CI, Br, F, -CH 2
OCH
3 , -CH 2
OCH
2
CH
3 , C 1
-C
2 alkyl, OCH 2
CH
2
R
3 and -OR4,wherein R3 is selected from -F, -OCH 3 , -N(CH 3
)CH
3 , unsaturated 5-membered rings containing at least one hetero atom wherein the hetero atom is selected from S, N and O, and wherein R4 is cyclopentyl, more preferrably, R3 is o10 imidazolyl, or one of X1, X2 or X3 is H and the other two taken together with the two carbon atoms and the bonds between them from the benzene ring to which they are substituted form a 5- membered saturated ring that contains at least one hetero atom selected from S, N and O. Preferably, when one of Xl, X2 or X3 is H, the other two are independently selected 15 from -OCH 3 and -CH2OCH 2
CH
3 . More preferrably, when one of X1, X2 or X3 is H, one or both of the other two is -0
C
1 alkyl, -O-C 2 alkyl or -O-C 3 alkyl. Another embodiment of the present invention concerns compounds of formula I, wherein X3 is H and X1 and X2 together with the two carbon atoms and the bonds 20 between them from the benzene ring to they are substituted form a 6-membered saturated ring that contains one hetero atom which is O. Another embodiment of the present invention concerns compounds of formula I, wherein one of the groups Xl, X2 or X3 is H at meta position, the group at ortho position is selected from C 1
-C
5 alkoxy and -OCH 2
CF
3 , and the group at para position is lower 25 alkoxy. Preferrably, X1, X2 or X3 group at ortho position is selected from ethoxy, isopropoxy and -OCH 2
CF
3 , and the group at para position is selected from methoxy and ethoxy. In this preferred embodiment, R1 is selected from piperazinyl and substituted piperazinyl. One embodiment of the present invention concerns compounds of formula I 30 wherein one of the groups X1, X2 or X3 is H at meta position, the group at the ortho WO 03/051359 PCT/EP02/13904 -9 position is C 1
-C
6 alkoxy and the group at the para position is -Cl, -Br or -F, or one of the groups X1, X2 or X3 is H at para position, and the two other groups at ortho position are
CI-C
6 alkoxy and the group at meta position is -Cl, -Br or -F. Another embodiment of the present invention concerns compound of formula II Y y 1
X
4 N 5 2 and the pharmaceutically acceptable salts and esters thereof, wherein R is -C=OR1, R1 is selected from C 1
-C
6 alkyl, saturated 5- and 6-membered rings, saturated 5- and 6 membered rings containing at least one hetero atom wherein the hetero atom is 10 selected from S, N and O and being optionally substituted with a group selected from
C
1
-C
2 alkyl, C 1
-C
3 alcohol, -N(CH 3
)CH
3 , -C=OCH 3 , and 5- and 6-membered rings containing at least one hetero atom wherein the hetero atom is selected from S, N, and O, X4 is selected from C 1
-C
2 alkyl, Cl-C 6 alkoxy, fluoroethoxy, -Cl, -Br, -F, -OCH 2 C=OOQ, 15 -0- C1-C 6 alkyl, -OCH2-cyclopropyl, -CH 2
OCH
2 -phenyl, saturated and unsaturated 5- and 6-membered rings, saturated and unsaturated 5- and 6 membered rings containing at least one hetero atom wherein the hetero atom is selected from S, N and O, wherein Q is selected from H, and C 1
-C
6 alkyl, 20 Y1 and Y2 are independently selected from -Cl, -Br, -NO 2 , -C= N and -C=H, with the proviso that where Y1 and Y2 are both -Cl, and R1 is -CH 3 or phenyl, then X4 is not -Cl. In a preferred embodiment, the present invention concerns compounds of formula II, wherein X4 is selected from -CH 3 , C 1
-C
6 alkoxy, -Cl, -Br, -OCH 2 C=OOQ, phenyl and WO 03/051359 PCT/EP02/13904 - 10 pyrrolidinyl, more preferrably,,X4 isselected from -CH 3 , C1-
C
6 alkoxy, -OCH 2 C=OOQ, phenyl and pyrrolidinyl, whereinQ is Hor,-CH 2
CH
3 . Another preferred embodiment of the present invention concerns compounds of formula II, wherein R1 is selected from -CH(CH 3
)CH
3 , piperazinyl, piperazinyl 5 substituted with a group selected from -CH 3 , -CH 2
CH
2 OH, and -C=OCH 3 , piperadinyl, and piperadinyl substituted with a group selected from -pyrrolidinyl, piperadinyl, and N(CH 3
)CH
3 . More preferrably, C 1
-C
6 alkyl in the compounds of formula II is selected from C 1 alkyl, C2 alkyl and C3 alkyl. 10 More preferrably, the present invention concerns compounds of formula II wherein Y1 and Y2 are independently selected from -Cl and -Br. Another preferred embodiment of the present invention concerns compounds of formula I, wherein X4 is C1-
C
6 alkoxy at ortho position, more preferrably, the C1- C 6 alkoxy is selected from ethoxy, isopropoxy and 2-fluoroethoxy. In this preferred 15 embodiment R1 is selected from piperazinyl and substituted piperazinyl. The present invention concerns compounds of formula I, selected from the group of: a) 1- [4,5-Bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro imidazol-1-yl] -2-methyl-propan- 1-one; b) 1- [4,5-Bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro 20 imidazol-1-yl] ethanone; c) 1-[4,5-Bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro imidazol- l-yl]-2,2-dimethyl-propan- 1-one; d) [4,5-Bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro-imidazol 1-yll -cyclopentyl-methanone; 25 e) [4,5-Bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro-imidazol 1 -yl] -cyclohexyl-methanone; f) [4,5-Bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro-imidazol 1-yl] -thiophen-2-yl-methanone; g) [4,5-Bis-(4-chloro-phenyl)-2- (2,4-dimethoxy-phenyl)-4,5-dihydro-imidazol 30 1-yl]j -isoxazol-5-yl-methanone; WO 03/051359 PCT/EPO2/13904 - 11 h) [4,5-Bis- (4-chloro-phenyl)-2- (2,4-dimethoxy-phenyl)-4,5-dihydro-imidazol 1-yl]-furan-2-yl-methanone; i) 1- [4,5-Bis-(4-chloro-phenyl)-2-(2,3-dimethoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-2-methyl-propan- 1-one; 5 j) [4,5-Bis- (4-chloro-phenyl)-2- (2,4-dimethoxy-phenyl)-4,5-dihydro-imidazol 1-yl]-(4-methyl-piperazin- l-yl)-methanone; k) [4,5-Bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro-imidazol 1-yl]-piperazin- 1-yl-methanone; 1) [4,5-Bis-(4-chloro-phenyl)-2- (2-fluoro-6-methoxy-phenyl)-4,5-dihydro 10 imidazol- 1-yl]-[4-(2-hydroxy-ethyl)-piperazin- l-yl] -methanone; m) 1- {4- [4,5-Bis-(4-bromo-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro imidazole- 1-carbonyl]-piperazin- l-yl}-ethanone; n) [4,5-Bis- (4-bromo-phenyl)-2- (2,4-dimethoxy-phenyl)-4,5-dihydro-imidazol 1-yl]- [4-(2-hydroxy-ethyl)-piperazin-1l-yl]-methanone; 15 o) [4,5-Bis- (4-chloro-phenyl)-2- (2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl] -[4-(2-hydroxy-ethyl)-piperazin-1-yl] -methanone hydrochloride; p) [4,5-Bis-(4-chloro-phenyl)-2- (2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl] -(4-methanesulfonyl-piperazin- 1-yl)-methanone; 20 q) [4,5-Bis- (4-chloro-phenyl)-2- (2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl] -[4-(2-hydroxy-ethyl)-piperazin-1-yl] -methanone; r) [4,5-Bis- (4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-morpholin-4-yl-methanone; s) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro 25 imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone; t) 1-{4- [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazole- 1-carbonyll -piperazin- 1-yl}-ethanone; u) 4- [4,5-Bis-(4-chloro-phenyl)-2- (2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazole- 1 -carbonyll -piperazin-2-one; 30 v) [4,5-Bis- (4-chloro-phenyl)-2- (2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-piperazin- 1-yl-methanone; w) 1- {4- [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 dihydro-imidazole- 1-carbonyl] -piperazin- 1-yl}-ethanone; x) [4,5-Bis- (4-chloro-phenyl)-2- (2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro 35 imidazol- 1-yl]-(4-methanesulfonyl-piperazin- 1-yl)-methanone; WO 03/051359 PCT/EPO2/13904 -12 y) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-(2,5-dimethyl-piperazin-1-yl)-methanone; z) 4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazole- 1-carboxylic acid bis-(2-hydroxy-ethyl)-amide; 5 aa) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl] -(4-ethyl-piperazin-1-yl)-methanone; bb) [ 1,4']Bipiperidinyl- l'-yl-[4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4 methoxy-phenyl)-4,5-dihydro-imidazol- 1-yl]-methanone; cc) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro 10 imidazol-1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; dd) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl]-(4-dimethylamino-piperidin-1l-yl)-methanone; ee) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-morpholin-4-yl-methanone; 15 ff) [4,5-Bis- (4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl]- (4-isopropyl-piperazin- 1 -yl)-methanone; gg) 4- [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 dihydro-imidazole- 1-carbonyl]-piperazin-2-one; hh) [4,5-Bis- (4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro 20 imidazol- 1-yl] -(4-hydroxymethyl-piperidin- l-yl)-methanone; ii) [4,5-Bis- (4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- l-yl]-[4-(2-hydroxy-ethyl)-piperidin- 1-yl]-methanone; jj) [4,5-Bis- (4-chloro-phenyl)-2- (2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- l-yl]-(3-methyl-piperazin- 1-yl)-methanone; 25 kk) 1- {4- [4,5-Bis- (4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 dihydro-imidazole- 1-carbonyl]-2-methyl-piperazin- 1-yl}-ethanone; 11) [4,5-Bis- (4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl] - (4-methanesulfonyl-3-methyl-piperazin- 1-yl)-methanone; mm) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro 30 imidazol-1l-yl]-(4-hydroxy-piperidin-1-yl)-methanone; nn) (4-Aminomethyl-piperidin-1-yl)-[4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy 4-methoxy-phenyl)-4,5-dihydro-imidazol-l-yl]-methanone; oo) [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1l-yl]-[4-(2-hydroxy-ethyl)-piperazin-1l-yl]-methanone; WO 03/051359 PCT/EPO2/13904 -13 pp) [4,5-Bis-(4-bromo-phenyl)-2- (2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl] -piperazin- 1 -yl-methanone; qq) [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl]- (4-methanesulfonyl-piperazin- 1-yl)-methanone; 5 rr) 1- {4- [4,5-Bis- (4-bromo-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazole- 1 -carbonyll -piperazin- l-yl -ethanone; ss) [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl]- (4-methyl-piperazin- 1-yl)-methanone; tt) 4-[4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro 10 imidazole-l1-carbonyll -piperazine- 1-carbaldehyde; uu) [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-(4-pyrrolidin- 1-yl-piperidin- 1-yl)-methanone; vv) [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-(4-dimethylamino-piperidin-1l-yl)-methanone; 15 ww) [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl] -(4-isopropyl-piperazin- 1 -yl)-methanone; xx) 4- [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazole- 1-carbonyl]-piperazin-2-one; and yy) [4,5-Bis-(4-bromo-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro 20 imidazol-1-yl] -piperazin- 1 -yl-methanone. In another embodiment, the present invention concerns compounds of formula I, selected from the group of: a) 1- {4-[4,5-Bis-(4-bromo-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 dihydro-imidazole- 1-carbonyl]-piperazin-1-yl}-ethanone; 25 b) [4,5-Bis-(4-bromo-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone; c) [4,5-Bis-(4-bromo-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone; d) [4,5-Bis-(4-bromo-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro 30 imidazol-1-yl]-morpholin-4-yl-methanone; e) [1,4']Bipiperidinyl- l'-yl-[4,5-bis-(4-bromo-phenyl)-2-(2-isopropoxy-4 methoxy-phenyl)-4,5-dihydro-imidazol-1l-yl]-methanone; f) [4,5-Bis-(4-bromo-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl]-(4-ethyl-piperazin-1-yl)-methanone; WO 03/051359 PCT/EPO2/13904 - 14 g) 4- [4,5-Bis-(4-bromo-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 dihydro-imidazole- 1-carbonyl] -piperazin-2-one; h) [4,5-Bis-(4-cyano-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- l-yl]-piperazin- 1 -yl-methanone; 5 i) 1-(4-{4,5-Bis-(4-chloro-phenyl)-2- [4-methoxy-2- (2-methoxy-ethoxy) phenyl]-4,5-dihydro-imidazole- 1-carbonyl}-piperazin- 1 -yl)-ethanone; j) 1-(4-{4,5-Bis-(4-chloro-phenyl)-2- [2-(2-fluoro-ethoxy)-4-methoxy-phenyl] 4,5-dihydro-imidazole- 1-carbonyl}-piperazin- 1-yl) -ethanone; k) 4- {4,5-Bis-(4-chloro-phenyl)-2- [2-(2-fluoro-ethoxy)-4-methoxy-phenyl]-4,5 10 dihydro-imidazole- 1 -carbonyl}-piperazin-2-one; 1) [4,5-Bis-(4-chloro-phenyl)-2- (2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-piperazin- 1 -yl-methanone hydrochloride; m) 4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazole- 1-carboxylic acid methyl-(2-methylamino-ethyl)-amide, 15 trifluoroacetic acid salt; n) 4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazole-1-carboxylic acid (2-dimethylamino-ethyl)-methyl-amide, trifluoroacetic acid salt; o) 4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro 20 imidazole-1-carboxylic acid (2-dimethylamino-ethyl)-amide, trifluoroacetic acid salt; p) 4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazole-1-carboxylic acid (2-amino-ethyl)-amide, trifluoroacetic acid salt; q) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro 25 imidazol-1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone hydrochloride; r) [4,5-Bis-(4-chloro-phenyl)-2-(4-methoxy-2-propoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-piperazin- 1-yl-methanone, trifluoroacetic acid salt; s) [4,5-Bis- (4-chloro-phenyl)-2- (2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl] -(4-methyl-piperazin- 1-yl)-methanone hydrochloride; 30 t) 4,5-Bis- (4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazole-l1-carboxylic acid (2-morpholin-4-yl-ethyl)-amide hydrochloride; u) 4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazole-l1-carboxylic acid (2-piperazin-1-yl-ethyl)-amide hydrochloride; v) [4,5-Bis-(4-chloro-phenyl)-2-(2-isobutoxy-4-methoxy-phenyl)-4,5-dihydro 35 imidazol-1-yl]-piperazin-1-yl-methanone hydrochloride; WO 03/051359 PCT/EP02/13904 - 15 w) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl] -( 3-methyl-piperazin- 1 -yl)-methanone hydrochloride; x) {4,5-Bis-(4-chloro-phenyl)-2- [4-methoxy-2-(2-methoxy-ethoxy)-phenyl] -4,5 dihydro-imidazol-1-yl}-piperazin-1-yl-methanone, trifluoroacetic acid salt; 5 y) {4,5-Bis-(4-chloro-phenyl)-2-[2-(2-fluoro-ethoxy)-4-methoxy-phenyl ] -4,5 dihydro-imidazol-1-yl}-piperazin-1-yl-methanone; z) {4,5-Bis-(4-chloro-phenyl)-2-[2-(2-fluoro-ethoxy)-4-methoxy-phenyl]-4,5 dihydro-imidazol-1-yl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone hydrochloride; 10 aa) 2-Amino- 1- {4- [4,5-bis- (4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy phenyl)-4,5-dihydro-imidazole- 1-carbonyl]-piperazin-1-yl}-ethanone; bb) 1-{4-[4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 dihydro-imidazole- 1-carbonyl] -piperazin-1-yl}-2-hydroxy-ethanone; cc) 1-{4-[4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 15 dihydro-imidazole- 1-carbonyl] -piperazin- 1-yl}-2,3-dihydroxy-propan- 1-one; dd) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-[4-(2,3-dihydroxy-propyl)-piperazin-1-yl] -methanone; ee) 4- [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 dihydro-imidazole-l1-carbonyl]-piperazine-l1-carboxylic acid dimethylamide; 20 ff) 4- [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 dihydro-imidazole- 1-carbonyl]-piperazine- 1 -carboxylic acid amide; gg) [4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-phenyl)-4,5-dihydro-imidazol- 1 yl]-piperazin- 1-yl-methanone; hh) [4,5-Bis-(4-chloro-phenyl)-2- (2,4-diethoxy-phenyl)-4,5-dihydro-imidazol- 1 25 yl] morpholin-4-yl-methanone; ii) [4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-phenyl)-4,5-dihydro-imidazol- 1 yl]- [4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone; jj) [4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-phenyl)-4,5-dihydro-imidazol- 1 yl]-(4-methyl-piperazin-1-yl)-methanone; 30 kk) 1- {4-[4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-phenyl)-4,5-dihydro imidazole-1-carbonyl]-piperazin-1-yl}-ethanone; 11) [4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-phenyl)-4,5-dihydro-imidazol- 1 yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone; mm) [4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-phenyl)-4,5-dihydro-imidazol- 1 35 yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; WO 03/051359 PCT/EPO2/13904 -16 nn) [4,5-Bis-(4-bromo-phenyl)-2- (2,4-diethoxy-phenyl)-4,5-dihydro-imidazol- 1 yl]-(4-methyl-piperazin- 1-yl)-methanone; oo) [4,5-Bis-(4-bromo-phenyl)-2-(2,4-diethoxy-phenyl)-4,5-dihydro-imidazol- 1 yl]-(4-ethyl-piperazin- l-yl)-methanone; 5 pp) [4,5-Bis-(4-bromo-phenyl)-2-(2,4-diethoxy-phenyl)-4,5-dihydro-imidazol- 1 yl]-morpholin-4-yl-methanone; qq) 4- [4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-phenyl)-4,5-dihydro-imidazole 1-carbonyl]-piperazine-1-carboxylic acid amide; rr) 4- [4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-phenyl)-4,5-dihydro-imidazole 10 1-carbonyl]-piperazine- 1-carboxylic acid dimethylamide; ss) [4,5-Bis-(4-chloro-phenyl)-2-(4-dimethylamino-2-ethoxy-phenyl)-4,5 dihydro-imidazol-1-yl] -piperazin-1-yl-methanone; tt) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-ethyl-phenyl)-4,5-dihydro imidazol- 1-yl]-piperazin- 1-yl-methanone; 15 uu) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methyl-phenyl)-4,5-dihydro imidazol- l-yl]-piperazin- 1-yl-methanone; vv) [4,5-Bis-(4-chloro-phenyl)-2-(4-ethyl-2-isopropoxy-phenyl)-4,5-dihydro imidazol- l-yl]-piperazin- 1 -yl-methanone; ww) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methyl-phenyl)-4,5-dihydro 20 imidazol- l-yl]-piperazin- 1 -yl-methanone; xx) 1-{4- [4,5-Bis-(4-chloro-phenyl)-2- (4-dimethylamino-2-ethoxy-phenyl)-4,5 dihydro-imidazole- 1 -carbonyl] -piperazin-1-yl}-ethanone; and yy) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-5-methyl-phenyl)-4,5-dihydro imidazol-1-yl]-piperazin-1-yl-methanone, trifluoroacetic acid salt. 25 In another embodiment, the present invention concerns compounds of formula I, selected from the group of: a) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-fluoro-phenyl)-4,5-dihydro imidazol-1l-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; b) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-fluoro-phenyl)-4,5-dihydro 30 imidazol- 1-yl]-(4-dimethylamino-piperidin-1-yl)-methanone; c) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-fluoro-phenyl)-4,5-dihydro imidazol-l-yl]-piperazin-1-yl-methanone; d) [4,5-Bis-(4-chloro-phenyl)-2-(4-fluoro-2-isopropoxy-phenyl)-4,5-dihydro imidazol-1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; WO 03/051359 PCT/EP02/13904 -17 e) [4,5-Bis-(4-chloro-phenyl)-2-(4-fluoro-2-isopropoxy-phenyl)-4,5-dihydro imidazol-l-yl]-(4-dimethylamino-piperidin-1-yl)-methanone; f) [4,5-Bis-(4-chloro-phenyl)-2-(4-fluoro-2-isopropoxy-phenyl)-4,5-dihydro imidazol-1l-yl]-(4-methyl-piperazin-1-yl)-methanone; 5 g) [4,5-Bis-(4-chloro-phenyl)-2-(4-fluoro-2-isopropoxy-phenyl)-4,5-dihydro imidazol-1-yl] -piperazin-1-yl-methanone; h) [4,5-Bis-(4-chloro-phenyl)-2-(4-fluoro-2-isopropoxy-phenyl)-4,5-dihydro imidazol-1l-yl]-(4-methanesulfonyl-piperazin- 1-yl)-methanone; i) 4- [4,5-Bis-(4-chloro-phenyl)-2-(4-fluoro-2-isopropoxy-phenyl)-4,5-dihydro 10 imidazole- 1-carbonyll -piperazin-2-one; j) [4,5-Bis-(4-chloro-phenyl)-2-chroman-8-yl-4,5-dihydro-imidazol- 1-yl] piperazin-1-yl-methanone; k) 4- [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-fluoro-phenyl)-4,5-dihydro imidazole- 1-carbonyll -piperazin-2-one; 15 1) [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-fluoro-phenyl)-4,5-dihydro imidazol- 1-yl]-morpholin-4-yl-methanone; m) [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-fluoro-phenyl)-4,5-dihydro imidazol-1l-yl]-(4-pyrrolidin- 1-yl-piperidin- 1-yl)-methanone; n) [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-fluoro-phenyl)-4,5-dihydro 20 imidazol-l-yl]-(4-dimethylamino-piperidin- l-yl)-methanone; o) [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-fluoro-phenyl)-4,5-dihydro imidazol-1-yl] -piperazin- 1-yl-methanone; p) [4,5-Bis-(4-chloro-phenyl)-2-(2-cyclopentyloxy-4-methoxy-phenyl)-4,5 dihydro-imidazol- l-yl]-piperazin- 1-yl-methanone; 25 q) {4,5-Bis-(4-chloro-phenyl)-2- [2-(2-dimethylamino-ethoxy)-4-methoxy phenyl]-4,5-dihydro-imidazol- 1-yl}-piperazin- 1-yl-methanone; r) {4,5-Bis-(4-chloro-phenyl)-2- [2-(2-imidazol-1-yl-ethoxy)-4-methoxy phenyl]-4,5-dihydro-imidazol- l-yl}-piperazin- 1-yl-methanone; s) [2-(4-Chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro 30 imidazol-1-yl] -piperazin- 1-yl-methanone hydrochloride; t) [2-(4-Chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro imidazol- 1 -yl] -(4-methyl-piperazin- 1 -yl)-methanone hydrochloride; u) [2-(4-Chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5.-dihydro imidazol- l-yl]-(4-pyrrolidin- 1 -yl-piperidin- 1 -yl)-methanone hydrochloride; WO 03/051359 PCT/EPO2/13904 - 18 v) [2-(4-Chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro imidazol- 1-yl]-morpholin-4-yl-methanone; w) 1- {4- [2-(4-Chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro imidazole- 1 -carbonyl] -piperazin- 1 -yl}-ethanone; 5 x) [2- (4-Chloro-2-ethoxy-phenyl)-4,5-bis- (4-chloro-phenyl)-4,5-dihydro imidazol- 1-yl]-[4-(2-hydroxy-ethyl)-piperazin- l-yl]-methanone hydrochloride; y) 4- [2-(4-Chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro imidazole- 1-carbonyl] -piperazin-2-one; 10 z) [4,5-Bis- (4-chloro-phenyl)-2-(4-ethoxy-2-isopropoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-piperazin- 1 -yl-methanone; aa) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-5-methoxy-phenyl)-4,5-dihydro imidazol-1-yl]-piperazin- 1-yl-methanone, trifluoroacetic acid salt; bb) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-5-methoxy-phenyl)-4,5-dihydro 15 imidazol- 1-yl] -(4-methanesulfonyl-piperazin- 1-yl)-methanone; cc) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-5-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-[4-(2-hydroxy-ethyl)-piperazin- l-yl]-methanone hydrochloride; dd) [4,5-Bis-(4-chloro-phenyl)-2-(2,5-diethoxy-phenyl)-4,5-dihydro-imidazol- 1 20 yl]-piperazin-1-yl-methanone hydrochloride; ee) [4,5-Bis-(4-chloro-phenyl)-2-(2,5-diethoxy-phenyl)-4,5-dihydro-imidazol- 1 yl]-(4-methanesulfonyl-piperazin- 1-yl)-methanone; f) [4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-isopropoxy-phenyl)-4,5-dihydro imidaz6ol-1-yl]- [4-(2-hydroxy-ethyl)-piperazin-l-yl]-methanone; 25 gg) 4- [4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-isopropoxy-phenyl)-4,5-dihydro imidazole- 1-carbonyl] -piperazin-2-one; hh) [4,5-Bis-(4-chloro-phenyl)-2-(5-ethoxy-2-isopropoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-piperazin-1-yl-methanone; ii) [4,5-Bis-(4-chloro-phenyl)-2-(5-ethoxy-2-isopropoxy-phenyl)-4,5-dihydro 30 imidazol- 1-yl]-(4-methanesulfonyl-piperazin- 1-yl)-methanone; jj) [4,5-Bis-(4-chloro-phenyl)-2-(5-ethoxy-2-isopropoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-[4-(2-hydroxy-ethyl)-piperazin- 1-yl ]-methanone hydrochloride; kk) 1- {4- [4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-isopropoxy-phenyl)-4,5 35 dihydro-imidazole- 1-carbonyl]-piperazin-1l-yl} -ethanone; WO 03/051359 PCT/EPO2/13904 - 19 11) 1- {4- [4,5-Bis- (4-chloro-phenyl)-2-(5-ethoxy-2-isopropoxy-phenyl)-4,5 dihydro-imidazole- 1-carbonyl]-piperazin- l-yl}-ethanone; mm) [4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-isopropoxy-phenyl)-4,5-dihydro imidazol-1-yl]-(4-pyrrolidin-1-yl-piperidin-1l-yl)-methanone; 5 nn) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-5-methoxy-phenyl)-4,5-dihydro imidazol-l-yl]-piperazin-1-yl-methanone, trifluoroacetic acid salt; oo) [4,5-Bis-(4-chloro-phenyl)-2-(2,4-diisopropoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-piperazin-1-yl-methanone; pp) [4,5-Bis-(4-chloro-phenyl)-2-(2,5-diisopropoxy-phenyl)-4,5-dihydro 10 imidazol-1-yl] -piperazin-1-yl-methanone hydrochloride; qq) 1- [4,5-Bis-(4-chloro-phenyl)-2-(2-methoxy-5-morpholin-4-yl-methyl phenyl)-4,5-dihydro-imidazol- 1-yl]-2-methyl-propan- 1-one; rr) 1- [4,5-Bis-(4-chloro-phenyl)-2-(3-hydroxymethyl-5-methoxy-phenyl)-4,5 dihydro-imidazol- 1-yl] -2-methyl-propan- 1-one; 15 ss) 1- [4,5-Bis-(4-chloro-phenyl)-2-(3-hydroxymethyl-5-methoxymethyl-phenyl) 4,5-dihydro-imidazol-1-yl] - ethanone; tt) 1-[4,5-Bis-(4-chloro-phenyl)-2-(3-methoxy-5-methoxymethyl-phenyl)-4,5 dihydro-imidazol- 1-yl]-2-methyl-propan- 1-one; uu) 3-[4,5-Bis-(4-chloro-phenyl)-l1-isobutyryl-4,5-dihydro-l1H-imidazol-2-yl]-5 20 methoxymethyl-benzoic acid; vv) 1- [4,5-Bis-(4-chloro-phenyl)-2-(5-ethoxymethyl-2,4-dimethoxy-phenyl)-4,5 dihydro-imidazol- 1-yl] -2-methyl-propan- 1-one; ww) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-6-methoxy-phenyl)-4,5-dihydro imidazol-1-yl]-piperazin-1-yl-methanone; and 25 xx) [4,5-bis-(4-chloro-phenyl)-2-(5-ethoxymethyl-2,4-dimethoxy-phenyl)-4,5 dihydro-imidazol-1-yl] -piperazin-1-yl-methanone. In a further embodiment, the present invention concerns compounds of formula I selected from the group of: a) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro 30 imidazol-1l-yl]-[4-(2-hydroxy-propyl)-piperazin-1-yl]-methanone; b) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl]-threo[4-(2-hydroxy- 1-methyl-propyl)-piperazin-1-yl] methanone; WO 03/051359 PCT/EP02/13904 - 20 c) [4,5-Bis-(4-chloro-phenyl)-2-( 2 -isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-erythro [4-(2-hydroxy-l1-methyl-propyl)-piperazin- l-yl] methanone; d) 1- {4- [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 5 dihydro-imidazole-l1-carbonyl]-piperazin- 1-yl}-propan-2-one; e) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-[1,4]diazepan-1-yl-methanone; f) 4- [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 dihydro-imidazole-l1-carbonyll -1-methyl-piperazin-2-one; 10 g) 1- {4- [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 dihydro-imidazole-l1-carbonyl]-piperazin- 1-yl} -2-methyl-propan- 1-one; h) 4- [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 dihydro-imidazole- 1-carbonyl]-piperazine- 1-carbaldehyde; i) 4- {4,5-Bis-(4-chloro-phenyl)-2- [4-methoxy-2-(2,2,2-trifluoro-ethoxy) 15 phenyl]-4,5-dihydro-imidazole- 1-carbonyl}-piperazin-2-one; j) 4- {4,5-Bis-(4-bromo-phenyl)-2- [4-methoxy-2-(2,2,2-trifluoro-ethoxy) phenyl]-4,5-dihydro-imidazole- 1-carbonyl}-piperazin-2-one; k) [4,5-Bis-(4-ethynyl-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 dihydro-imidazol- 1-yl] -(4-pyrrolidin- 1 -yl-piperidin- 1-yl)-methanone; 20 1) 1- {4- [2-(5-Chloro-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5 dihydro-imidazole-1-carbonyll -piperazin-1 -yl }-ethanone; and m) [5-(4-Chloro-phenyl)-4-(4-ethynyl-phenyl)-2-(2-isopropoxy-4-methoxy phenyl)-4,5-dihydro-imidazol-1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl) methanone. 25 In another embodiment, the present invention concerns compounds of formula II selected from the group consisting of: a) 1- [4,5-Bis-(4-chloro-phenyl)-2-(2-methoxy-phenyl)-4,5-dihydro-imidazol- 1 yl]-2-methyl-propan- 1-one; b) 1-[4,5-Bis-(4-chloro-phenyl)-2-p-tolyl-4,5-dihydro-imidazol-1 -yl]-ethanone; 30 c) {4- [4,5-Bis-(4-chloro-phenyl)- 1-isobutyryl-4,5-dihydro- 1H-imidazol-2-yl] phenoxy}-acetic acid ethyl ester; d) {4- [4,5-Bis-(4-chloro-phenyl)- 1-isobutyryl-4,5-dihydro- 1H-imidazol-2-yl] phenoxy} -acetic acid; WO 03/051359 PCT/EPO2/13904 -21 e) 2-Methyl-1- [2,4,5-tris-(4-chloro-phenyl)-4,5-dihydro-imidazol- 1-yl] -propan 1-one; f) 1- [4,5-Bis-(4-chloro-phenyl)-2- (4-methoxy-phenyl)-4,5-dihydro-imidazol- 1 yl] -ethanone; 5 g) [2-(2-Chloro-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol- 1-yl] piperazin- 1-yl-methanone; h) [2-(3-Bromo-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol- 1-yl ] piperazin- 1-yl-methanone; i) [2-Biphenyl-3-yl-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol- 1-yl]-(4 10 methyl-piperazin- 1-yl)-methanone; j) [4,5-Bis-(4-chloro-phenyl)-2- (3-pyrrolidin- 1-yl-phenyl)-4,5-dihydro imidazol- l-yl]-piperazin- 1 -yl-methanone; k) [4,5-Bis- (4-bromo-phenyl)-2-(2-methoxy-phenyl)-4,5-dihydro-imidazol- 1 yl]-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone; 15 1) 1- [5- (4-Chloro-phenyl)-2- (4-methoxy-phenyl)-4- (4-nitro-phenyl)-4,5 dihydro-imidazol- 1-yl]-2-methyl-propan- 1-one; m) 1- [4-(4-chloro-phenyl)-2-(4-methoxy-phenyl)-5-(4-nitro-phenyl)-4,5 dihydro-imidazol- 1-yl] -2-methyl-propan- 1-one; n) 1- [4,5-Bis-(4-chloro-phenyl)-2- (2-isopropoxy-phenyl)-4,5-dihydro-imidazol 20 1-yl]-2-methyl-propan- 1-one; o) [4,5-Bis- (4-chloro-phenyl)-2- (2-isopropoxy-phenyl)-4,5-dihydro-imidazol- 1 yl ]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; p) [4,5-Bis-(4-chloro-phenyl)-2- (2-isopropoxy-phenyl)-4,5- dihydro-imidazol- 1 yl] -piperazin- 1-yl-methanone; 25 q) [4,5-Bis- (4-chloro-phenyl)-2- (2-isopropoxy-phenyl)-4,5- dihydro-imidazol- 1 yl]- (4-dimethylamino-piperidin- 1-yl)-methanone; r) [1,4'] Bipiperidinyl- l'-yl- [4,5-bis- (4-chloro-phenyl)-2-(2-isopropoxy-phenyl) 4,5-dihydro-imidazol- 1-yl]-methanone; s) [4,5-Bis- (4-chloro-phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro-imidazol- 1 30 yl] -[4- (2-hydroxy-ethyl)-piperazin- 1-yl] -methanone; t) {4,5-Bis- (4-chloro-phenyl)-2- [2- (2-methyl-butoxy)-phenyl]-4,5-dihydro imidazol- 1-yl}-piperazin- 1-yl-methanone; u) [4,5-Bis-(4-chloro-phenyl)-2- (2-pentyloxy-phenyl)-4,5-dihydro-imidazol- 1 yl] -piperazin- 1-yl-methanone; WO 03/051359 PCT/EPO2/13904 - 22 v) [4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-phenyl)-4,5-dihydro-imidazol- 1-yl] piperazin-1-yl-methanone, trifluoroacetic acid salt; w) [4,5-Bis-(4-chloro-phenyl)-2-(3-isopropoxy-phenyl)-4,5-dihydro-imidazol- 1 yll -piperazin-1-yl-methanone, trifluoroacetic acid salt; 5 x) 1- {4- [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-phenyl)-4,5-dihydro-imidazole 1-carbonyl]-piperazin-1l-yl}-ethanone; y) [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-phenyl)-4,5-dihydro-imidazol- 1-yl] [4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone; z) 1- {4- [4,5-Bis-(4-bromo-phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro 10 imidazole-1-carbonyl]-piperazin- 1-yl}-ethanone; and aa) [4,5-Bis-(4-bromo-phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro-imidazol-1 yl]- [4- (2-hydroxy-ethyl)-piperazin- 1-yl] -methanone. The compounds according to the present invention show strong anti-tumor activity against various tumor cell lines. This anti-tumor activity indicates that tcompounds of the 15 present invention and pharmaceutically acceptable salts thereof can be anti-tumor agents. One embodiment of the present invention is also a pharmaceutical composition comprising a compound according to the invention as an active ingredient and a pharmaceutical acceptable carrier. Preferrably, the pharmaceutical composition according to the invention is suitable for oral or parenteral administration. 20 The pharmaceutical compositions may be administered orally, for example in the form of tablets, coated tablets, dragdes, hard or soft gelatine capsules, solutions, emulsions or suspensions. Administration can also be carried out rectally, for example using suppositories; locally or percutaneously, for example using ointments, creams, gels or solutions; or parenterally, for example using injectable solutions. 25 For the preparation of tablets, coated tablets, drag6es or hard gelatine capsules the compounds of the present invention may be admixed with pharmaceutically inert, inorganic or organic excipients. Examples of suitable excipients for tablets, drag6es or hard gelatine capsules include lactose, maize starch or derivatives thereof, talc or stearic acid or salts thereof. 30 Suitable excipients for use with soft gelatine capsules include for example vegetable oils, waxes, fats, semi-solid or liquid polyols etc.; according to the nature of the active WO 03/051359 PCT/EPO2/13904 - 23 ingredients it may however be the case that no excipient is needed at all for soft gelatine capsules. For the preparation of solutions and syrups, excipients which may be used include for example water, polyols, saccharose, invert sugar and glucose. 5 For injectable solutions, excipients which may be used include for example water, alcohols, polyols, glycerine, and vegetable oils. For suppositories, and local or percutaneous application, excipients which may be used include for example natural or hardened oils, waxes, fats and semi-solid or liquid polyols. 10 The pharmaceutical compositions may also contain preserving agents, solubilising agents, stabilising agents, wetting agents, emulsifiers, sweeteners, colorants, odorants, salts for the variation of osmotic pressure, buffers, coating agents or antioxidants. They may also contain other therapeutically valuable agents. In summary, a pharmaceutical formulation for oral administration may be granule, 15 tablet, sugar coated tablet, capsule, pill, suspension or emulsion, which for parenteral injection, for example, intravenously, intramuscularly or subcutaneously, may be used in the form of a sterile aqueous solution which may contain other substances, for example, salts or glucose to make the solution isotonic. The anti-tumor agent can also be administered in the form of a suppository or pessary, or they may be applied topically in 20 the form of a lotion, solution, cream, ointment or dusting powder. The present invention concerns also the use of compound as above described for the preparation of a medicament, more preferrably a medicament for the treatment or control of cell proliferative disorders, most preferrably, a medicament for the treatment or control of cancer. 25 For example, they are useful in treating or controling of breast, colon, lung or prostate tumors. A further embodiment of the present invention concerns a method for treating a cell proliferative disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to the present invention. More 30 preferrably the method according to the invention concerns a method wherein the cell WO 03/051359 PCT/EPO2/13904 - 24 proliferative disorder is cancer and most preferrably a method wherein the cancer is breast, colon, lung or prostate tumors. Finally the present invention concerns the compounds of formula I and the compounds of formula II for use in therapy. 5 Compounds of the present invention as exemplified advantageously show IC50s from about 70 hM to about 100 mM. A therapeutically effective amount of a compound in accordance with this invention means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of to10 a therapeutically effective amount is within the skill in the art. The therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and may be determined in a manner known in the art. Such dosage will be adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the 1is condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, should be appropriate, although the upper limit maybe exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral 20 administration, it may be given as continuous infusion. The compounds of the present invention can be prepared according to the following Schemes in accordance to the process provided. Started compounds are known in the art or are commercially available. The following definitions are provided as applicable to the synthesis schemes: 25 V1, V2, V3, V4, V5 are each independently selected from Hydrogen, -OV6, -SV7, NV8V9, -CONV8V9, -COOV10, halogen, nitro, trifluoromethyl, C 1
-C
6 alkyl, which optionally may be substituted by V11, and cycloalkyl; V1, V2 together may form part of a heterocycle with one or more heteroatoms, which optionally may be substituted by VIO.
WO 03/051359 PCT/EPO2/13904 - 25 V2, V3 together may form part of a heterocycle with one or more hetereoatoms, which optionally may be substituted by V10. Y1, Y2 are each independently selected from-C1, -Br, nitro, cyano; and-C=CH. V, is selected from COV12 and CONV13V14, 5 V6 is selected from the group of hydrogen, C 1
-C
6 alkyl, which optionally may be substituted by V11, and cycloalkyl; V7 is selected from the group ofhydrogen, andC 1
-C
6 alkyl; V8, V9 are each independently selected from the group of hydrogen, C 1
-C
6 alkyl, and cycloalkyl; 10 V8, V9 together may form part of a heterocycle with one or more hetereoatoms; V10 is selected from the group of hydrogen, C 1
-C
6 alkyl, and cycloalkyl; V11I is selected from the group of-CONV8V9, -NV8V9, -COOV10, aryl, halogen,
C
1
-C
6 alkoxy, morpholinyl, andheterocycles; V12 is selected from the group of hydrogen,C 1
-C
6 alkyl, cycloalkyl, aryl, heterocycle, 15 andheteroaryl; V13 and V14 are independently selected from the group of C 1
-C
6 alkyl, cycloalkyl,C 1
-C
4 alkyl substituted by V11; or V13 and V14 together may form part of a hetercycle such as morpholine, piperidine, pyrrolidine and piperazine; The piperazine maybe substituted by C 1
-C
6 alkyl, 20 hydroxyalkyl, acyl, acyl substituted with hydroxy and amino, alkylsulfonyl, CONH2, CONV8V9, keto, hydroxy; The piperidine may be substituted by dialkyl amine, pyrrolidine, orpiperidine.
WO 03/051359 PCT/EPO2/13904 - 26 Scheme I N I I HN 0 HCI VS V1 HCI, EtOH V V V4 * V 2 V4 * V2
V
3
V
s 3 2 3 Yi
NH
2 EtOHNH 2 N -NNH 4 V Vs V 4 HNV V 22 1 5 A compound of formula 2, a known compound or a compound prepared by known methods, is converted to a compound of formula 3 using hydrogen chloride gas in ethanol 5 over a period of several hours to several weeks. A formula of compound 3 is then reacted with a compound of formula 4 in a solvent such as ethanol, at a temperature of 60 to 100 0 C to afford a compound of formula 5. When V is COV12, a compound of formula 5 is reacted with a compound of formula CICOV12 (a known compound or a compound prepared by known methods) at 0 0 C to 10 25 0 C in the presence a base such as triethylamine to give a compound of formula 1. When V is CONV13V14(providing that NHV13V14 is a known compound or a compound prepared by known methods), a compound of formula 5 is reacted with phosgene at 0 0 C in the presence of triethylamine followed by the treatment of a compound of formula HNV13V14 to afford a compound of formula 1. 15 WO 03/051359 PCT/EPO2/13904 - 27 Scheme II Y1 Y1 y V2 V1 V 2 ,NN v5N
N
V3 V3 5 6 N N ,. ~V4 V5~ 4
V
4 Y2 27 Y1
V
1
V
2 N I ViV3 - N V15 As set forth in Scheme II, when V15 substituted piperazines are not commercially available (V15 may be acyl, acyl substituted with hydroxyl, amino, protected amino and 5 sulfonyl), a compound of formula 7 is prepared as follows: a compound of formula 5 is reacted with phosgene and triethylamine followed by the treatment of piperazine to afford a compound of formula 6. A compound of 6 is reacted with V15X to give a compound of formula 7. As set forth in Scheme III, a compound of formula 8 can be prepared from a 10 compound of formula 6 by the reaction of phosgene and triethylamine followed by the treatment of NHV8V9, a known compound or a compound prepared by known methods. 15 WO 03/051359 PCT/EP02/13904 - 28 Scheme III y1 Y1 Vs V4 V1 V2 N O N O N2 2 V5 V 4 I ,V5 V 4 CNI -H 6V 8- N 8 V9 The meso-1,2-diamine of formula 4 (Y1 = Y2) can be prepared according to the literature procedures (see Jennerwein, M. et al. Cancer Res. Clin. Oncol. 1988, 114, 347 5 58; Vogtle, F.; Goldschmitt, E. Chem. Ber. 1976, 109, 1-40). If it is desired to prepare a compound of formula 4 wherein Y1 ? Y2, modifications to the existing procedure can be made. An equal molar mixture of the benzaldehydes and meso-1,2-bis-(2-hydroxy-phenyl)-ethane-1,2-diamine can be used to afford a mixture of 1,2-diamines (Scheme IV). Knalker, H. J., et al. Tetrahedron Letters 1998, 39, p. 9407. It 10 was then reacted with di-t-butyldicarbonate in the presence of dimethylaminopyridine to give a compound of formula 9 after HPLC purification. Compound 9 is then converted to a compound of formula 4 by the treatment of hydrobromic acid in hot acetic acid. 15 20 WO 03/051359 PCT/EPO2/13904 - 29 Scheme IV Y1 10 y1 O 0
NH
2 Y2 + 3 NH 2 OH H
NH
2 where in the first structure y' = Y2; in the second structure yi = Y2 but
NH
2 not = that of the first structure; in the third structure Y1 not =Y2 OH Y1 Y - o
NH
2 N
NH
2 1 N 0 y2 Y2 4 9 If it is desired to prepare a compound of formula 2 which is not commercially available, many synthetic methods known in the art can be employed. Suitable processes 5 for synthesizing these benzonitriles are provided in the examples. Following schemes illustrate some of these methods. A compound of formula 11 (VI6 can be any suitable group such as V1, V2, V3, V4, or V5) can be prepared by alkylation of a compound of formula 10 with V6X (X = Cl, Br, I) using conventional methods (scheme V). The phenoxide anion is generated by a base 10 such as cesium carbonate or potassium carbonate. The reaction typically is carried out in refluxing acetone. V6 can also be introduced using Mitsunobu reaction (see for example, Hughes, D. L. Org. React. 1992, 42, 335-656).
WO 03/051359 PCT/EP02/13904 - 30 Scheme V N N II II V6X, base OH or OV6 V16 Mitsunobu ViB 10 11 A compound of formula 12 (V16 can be any suitable group such as V1, V2, V3, V4, or V5) can be converted into the benzonitrile 13 using literature procedures (Karmarkar, S. 5 N; Kelkar, S. L.; Wadia, M. S. Synthesis 1985, 510-512; Bergeron, R. J. et al. J. Med. Chem. 1999, 42, 95-108). V group can then be introduced using V6X (X = Cl, Br, I) or Mitsunobu reaction to give the benzonitrile 13 (scheme VI). Scheme VI N o II OH 1. NaOAc, EtNO 2 , AcOH \
O
V6 2 VBX, base V1 or V16 Mitsunobu 13 10 12 A compound of formula 15 can be prepared by bromination or iodination of phenol 14 (Scheme VII), (V16 can be any suitable group such as VI, V2, V3, V4, or V5). Reaction conditions such as N-bromosuccinamide/tetrahydrofuran or iodine/thallium(I) acetate can be utilized (see for example, Carreno, M. C.; Garcia Ruano, J. L.; Sanz, G.; Toledo, M. A.; 15 Urbano, A. Synlett 1997, 1241-1242; Cambie, R. C.; Rutledge, P. S.; Smith-Palmer, T.; Woodgate, P. D. J. Chem. Soc., Perkin Trans. 1 1976, 1161-4). V5 group can then be introduced using V6X (X = Cl, Br, I) or Mitsunobu reaction. Methods of converting aromatic halides to the corresponding nitriles are known in the art (see for example, Okano, T.; Iwahara, M.; Kiji, J., Synlett 1998, 243). Cyanation of the halide 15 (X'= Br, I) 20 can be accomplished using zinc cyanide with a catalyst such as tetrakis(triphenylphosphine)palladium (0). Solvents such dimethylformamide can be used and the reaction temperature is between 80-110 oC.
WO 03/051359 PCT/EP02/13904 -31 Scheme VII 1 V6X, base N Xor I OH NBS, THF OH Mitsunobu OV 6 12, TIOAc 2 Zn(CN) 2 , Pd(0) Vi6 V1 6 V 14 15 13 In scheme VIII, amination of aromatic halide 16 using HNV7V8 and palladium catalyst can be utilized to provide the benzonitrile of formula 17 (see for example, Harris, 5 M. C.; Geis, 0.; Buchwald, S. L. J. Org. Chem. 1999, 64, 6019). Scheme VIII N N II II Pd(0), HNRIR1 2 X NV8V9 16 17 A compound of formula 13 (V16can be any suitable group such as V1, V2, V3, V4, or 10 V5) can be prepared by nucleophilic substitution of 2-halobenzonitrile 18 (scheme IX). (see for example, X = F: Wells, K. M.; Shi, Y.-J.; Lynch, J. E.; Humphrey, G. R.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1996, 37, 6439-6442; X = NO2: Harrison, C. R.; Lett, R. M.; McCann, S. F.; Shapiro, R.; Stevenson, T. M. WO 92/03421, 1992). 15 Scheme IX N N II I OV6 X -> X = F, N0 2 V16
V
16 ie 18 13 WO 03/051359 PCT/EPO2/13904 -32 To prepare the benzonitrile of formula 21 wherein V1, V2, V3, V4, or V5 = OV6, sequential alkylation of the diol 19 with suitable V6X (X = CI, Br, I) are used. The bromides 20 are then converted to the nitriles 21 using zinc cyanide and Pd(0) catalyst (scheme X). 5 Scheme X N Br X' V6X, base Zn(CN) 2 , Pd(0) OH OV6 - ov
|OV
6 HO OV6 19 20 OVB 21 Certain of the following Examples refer to Examples provided in U.S. Provisional application Serial No. 60/341,729. The Examples of these Provisional applications are incorporated herein by reference. 10 The present invention encompasses the following Examples. For structural formulas shown, it is understood that oxygen and nitrogen atoms with available elections have a hydrogen bound thereto, as indicated by compound name. The following examples illustrate the preferred methods for the preparation of the compounds of the present invention, which are not intended to limit the scope of the invention thereto. 15 WO 03/051359 PCT/EPO2/13904 - 33 EXAMPLES Example 1 1-[4,5-Bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro-imidazol-1 yl] -2-methyl-propan-1-one 0 _o CI 0 N0O N 5 CI Hydrogen chloride gas was passed through a solution of 2, 4-dimethoxy-benzonitrile (5.20 g, 32 mmol) in anhydrous ethanol (200 mL) at 0 oC. After 7 h, hydrogen chloride gas was stopped and the reaction mixture was stirred at room temperature overnight. The solvent was removed and the residue was triturated in diethyl ether to afford ethyl 2,4 10 dimethoxy-benzimidate hydrochloride (4.5 g, 57%). It was used without further purification. A solution of meso-1,2-bis-(4-chloro-phenyl)-ethane-1,2-diamine (1.21 g, 4.30 mmol, prepared according to the procedure described by Jennerwein, M. et al. Cancer Res. Clin. Oncol. 1988, 114, 347-8; Vogtle, F.; Goldschmitt, E. Chem. Ber. 1976, 109, 1-40) and 15 ethyl 2,4-dimethoxy-benzimidate hydrochloride (1.58 g, 6.43 mmol) in ethanol (30 mL) was heated at reflux for 16 h. The reaction mixture was basified with sodium bicarbonate solution (10 mL) and extracted with ethyl acetate. The organic extracts were washed with brine and dried over anhydrous sodium sulfate. The solids were then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash 20 chromatography (Biotage system, KP-Sil M 32-63pm, 60 A silica gel) eluting with 2-6% methanol in methylene chloride yielded 4,5-bis-(4-chloro-phenyl)-2-(2, 4-dimethoxy phenyl)-4,5-dihydro-1H-imidazole (1.10 g, 60%). Isobutyryl chloride (19 pL, 0.18 mmol) was added to a solution of triethylamine (25 pL, 0.18 mmol) and 4,5-bis-(4-chloro-phenyl)-2-(2, 4-dimethoxy-phenyl)-4,5-dihydro 25 1H-imidazole (70 mg, 0.164 mmol). The reaction mixture was stirred at room temperature for 2 h. It was diluted with methylene chloride and washed with water and brine, and dried over sodium sulfate. The solvents were removed under reduced pressure WO 03/051359 PCT/EP02/13904 - 34 and chromatography of the residue over silica gel using 0.5-1% methanol in methylene chloride gave 1- [4,5-bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro imidazol-1-yl]-2-methyl-propan-1-one. HR-MS (EI, m/z) calculated for C27H26N203C2 (M+) 496.1320, observed 496.1319. 5 Example 2 In a similar manner as described in example 1, the following compounds were prepared. a)1- [4,5-Bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro-imidazol-1 10 yl] ethanone. HR-MS (EI, m/z) calculated for C25H22N203C2 (M+) 468.1007, observed 468.1020 0 CI-_ N O0 N Cl b)1-[4,5-Bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro-imidazol-1 yl]-2,2-dimethyl-propan-1-one. HR-MS (EI, m/z) calculated for C28H28N203C2 (M+) 15 510.1477, observed 510.1476. c)[4,5-Bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro-imidazol-1-yl] cyclopentyl-methanone. HR-MS (EI, m/z) calculated for C29H28N203C12 (M+) 522.1477, observed 522.1470. d)[4,5-Bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro-imidazol-1 20 yl]-cyclohexyl-methanone. HR-MS (EI, m/z) calculated for C30H30N203C2 (M+) 536.1633, observed 536.1633. e)[4,5-Bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro-imidazol- 1-yl] thiophen-2-yl-methanone. HR-MS (EI, m/z) calculated for C28H20N203C12S [(M 2H)+] 534.0572, observed 534.0566.
WO 03/051359 PCT/EP02/13904 - 35 f)[4,5-Bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro-imidazol-1-yl] isoxazol-5-yl-methanone. HR-MS (EI, m/z) calculated for C27H21N304Cl2 (M+) 521.0909, observed 521.0892. g)[4,5-Bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro-imidazol- 1 5 yl]-furan-2-yl-methanone. HR-MS (EI, m/z) calculated for C28H20N204C12 [(M-2H)+] 518.0800, observed 518.0802. h) 1-[4,5-Bis-(4-chloro-phenyl)-2-(2-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl] 2-methyl-propan-1-one. HR-MS (EI, m/z) calculated for C26H25N202C2 [(M+H)+] 467.1289, observed 467.1295 C / 10 10 11t i) 1- [4,5-Bis-(4-chloro-phenyl)-2-p-tolyl-4,5-dihydro-imidazol-1-yl] -ethanone. HR MS (El, m/z) calculated for C24H20N20C12 (M+) 422.0953, observed 422.0950. j) {4-[4,5-Bis-(4-chloro-phenyl)- 1-isobutyryl-4,5-dihydro- 1H-imidazol-2-yl] phenoxy}-acetic acid ethyl ester. HR-MS (ES, m/z) calculated for C29H29N204C12 15 [(M+H)+] 539.1499, observed 539.1506. The starting ethyl (4-cyano-phenoxy)-acetate was prepared from 4-hydroxy-benzonitrile and ethyl bromoacetate as described in Kirkiacharian, S.; Goma, J. R. et al. Ann. Pharm. Fr. 1989, 47, 16-23. k) {4- [4,5-Bis-(4-chloro-phenyl)- 1-isobutyryl-4,5-dihydro- 1H-imidazol-2-yl] phenoxy} -acetic acid was prepared by hydrolysis of {4- [4,5-bis-(4-chloro-phenyl)-1 20 isobutyryl-4,5-dihydro- lH-imidazol-2-yl]-phenoxy} -acetic acid ethyl ester. HR-MS (ES, m/z) calculated for C27H25N204C2 (M+) 511.1186, observed 511.1191. 1)2-Methyl-1-[2,4,5-tris-(4-chloro-phenyl)-4,5-dihydro-imidazol-l-yl]-propan-1 one. HR-MS (FAB, m/z) calculated for C25H22N2OC13 [(M+H)+] 471.0797, observed 471.0814.
WO 03/051359 PCT/EP02/13904 - 36 m) 1-[4,5-Bis-(4-chloro-phenyl)-2-(4-methoxy-phenyl)-4,5-dihydro-imidazol- 1-yl] ethanone. HR-MS (FAB, m/z) calculated for C24H21N202C2 [(M+H)+] 439.0980, observed 439.0967. Cl / CI 5 n) 1- [4,5-Bis-(4-chloro-phenyl)-2-(2,3-dimethoxy-phenyl)-4,5-dihydro-imidazol- 1 yl]-2-methyl-propan-1-one. HR-MS (ES, m/z) calculated for C27H27N203C12 [(M+H)+] 497.1393, observed 497.1398 Example 3 10 [4,5-Bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro-imidazol- 1-yl] (4-methyl-piperazin- 1-yl)-methanone clI -' o C0 N N N \/- 0 0\ CI N I Phosgene (1.31 mL, 2.53 mmol, 1.93 M in toluene) was added dropwise to a cooled (0 oC) mixture of triethylamine (0.37 mL, 2.64 mmol) and 4,5-bis-(4-chloro-phenyl)-2 15 (2,4-dimethoxy phenyl)-4,5-dihydro-1H-imidazole (225 mg, 0.53 mmol, example 1) in THF (5 mL). The reaction mixture was stirred for 2.5 h and evaporated. The residue was kept under high vacuum for 30 min and was redissovled in methylene chloride (10 mL). The slurry was added dropwise to a solution of N-methylpiperazine (1.05 g, 10.48 mmol) in methylene chloride (5 mL). After 1 h, the reaction was worked up with aqueous sodium 20 bicarbonate and extracted with methylene chloride. The organic extracts were washed with water and brine, and dried over sodium sulfate. Evaporation of the solvents and chromatography of the residue over silica gel using 1-4% methanol in methylene chloride WO 03/051359 PCT/EP02/13904 - 37 gave 4,5-bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro-imidazol- l-yl] -(4 methyl-piperazin-1-yl)-methanone. HR-MS (ES, m/z) calculated for C29H31N403C2 [(M+H)+] 553.1768, observed 553.1773. 5 Example 4 In a similar manner as described in example 1 and 3, the following compounds were prepared. a)[2-(2-Chloro-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol- 1-yl] piperazin-1-yl-methanone. HR-MS (ES, m/z) calculated for C26H24N4OC13 [(M+H)+] 10 513.1009, observed 513.1013 CI C1 ~ l I=o C1 - N C N b)[2-(3-Bromo-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl] piperazin-1-yl-methanone. HR-MS (ES, m/z) calculated for C26H24N4OC12Br [(M+H)+] 557.0505, observed 557.0506. 15 c)[2-Biphenyl-3-yl-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl] -(4 methyl-piperazin- 1-yl)-methanone. HR-MS (ES, m/z) calculated for C33H31N40C12 [(M+H)+] 569.1870, observed 569.1875. d) [4,5-Bis-(4-chloro-phenyl)-2-(3-pyrrolidin-1-yl-phenyl)-4,5-dihydro-imidazol-1 yl]-piperazin- 1 -yl-methanone was synthesized from 3-pyrrolidinobenzonitrile (described 20 in the previous patent). HR-MS (ES, m/z) calculated for C30H32N50C12 [(M+H)+] 548.1979, observed 548.1980. e)[4,5-Bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro-imidazol-1-yl] piperazin-1-yl-methanone. HR-MS (ES, m/z) calculated for C28H29N403C12 [(M+H)+] 539.1610 observed 539.1613 WO 03/051359 PCT/EP02/13904 -38 CIN O - 00% CI C N f) [4,5-Bis-(4-chloro-phenyl)-2-(2-fluoro-6-methoxy-phenyl)-4,5-dihydro-imidazol 1 -yl] -[4-(2-hydroxy-ethyl)-piperazin- 1 -yl] -methanone. HR-MS (ES, m/z) calculated for C29H30N403FC12 [(M+H)+] 571.1674, observed 571.1678. 5 g)1- {4- [4,5-Bis-(4-bromo-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro imidazole-1-carbonyl]-piperazin-1-yl}-ethanone. HR-MS (ES, m/z) calculated for C30H31N404Br2 [(M+H)+] 669.0707, observed 669.0710. h) [4,5-Bis-(4-bromo-phenyl) -2-(2,4-dimethoxy-phenyl)-4,5-dihydro-imidazol- 1 yl]-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone. HR-MS (ES, m/z) calculated for 10 C30H33N404Br2 [(M+H)+] 671.0863, observed 671.0870. i)[4,5-Bis-(4-bromo-phenyl)-2-(2-methoxy-phenyl)-4,5-dihydro-imidazol- 1-yl]-[4 (2-hydroxy-ethyl)-piperazin- 1 -yl] -methanone. HR-MS (ES, m/z) calculated for C29H31N403Br2 [(M+H)+] 641.0758, observed 641.0765 Br /O Br N 0 15 Example 5 1- [5-(4-chloro-phenyl)-2-(4-methoxy-phenyl)-4-(4-nitro-phenyl)-4,5-dihydro imidazol- 1-yl]-2-methyl-propan- 1-one and 1-[4-(4-Chloro-phenyl)-2-(4-methoxy phenyl)-5-(4-nitro-phenyl)-4,5-dihydro-imidazol- 1-yl]-2-methyl-propan- 1-one 20 To a solution of meso-1,2-bis-(2-hydroxy-phenyl)-ethane-1,2-diamine (5.38 g, 22 mmol, prepared according to the procedure described by Vogtle, F.; Goldschmitt, E.
WO 03/051359 PCT/EPO2/13904 -39 Chem. Ber. 1976, 109, 1-40) in acetonitrile (50 mL) were added 4-nitrobenzaldehyde (3.33 g, 22 mmol) and 4-chlorobenzaldehyde (3.31 g, 23.5 mmol). The reaction mixture was heated at gentle reflux for 12 h. Upon cooling to room temperature, the solvent was removed in vacuo. The residue was suspended in 3 N sulfuric acid and the reaction 5 mixture was heated at reflux for 2 h. Upon cooling to room temperature, the salicylaldehyde by-product was removed by extraction with diethyl ether (1 x 10 mL). The clear aqueous layer was neutralized with 5% sodium hydroxide solution to precipitate out the diamine product (pH >9). Crude 1-(4-chloro-phenyl)-2-(4-nitro-phenyl)-ethane-1,2 diamine (4.61 g) was collected by filtration, washed with water, and dried under vacuum 10 overnight. Di-t-butyldicarbonate (6.77 g, 31 mmol) was added to a solution of crude 1-(4 chloro-phenyl)-2-(4-nitro-phenyl)-ethane-1,2-diamine (2.92 g) in acetonitrile (100 mL) in an ice-bath. Dimethylaminopyridine (122 mg, 1 mmol) was added and the ice-bath was removed. After 1 h, more dimethylaminopyridine (122 mg, 1 mmol) was added. After a 15 few minutes, the mixture was warmed up to 50 oC over 10 min. Evaporation of the solvents and reversed phase HPLC purification of the crude mixture gave 4-(4-chloro phenyl)-5-(4-nitro-phenyl)-2-oxo-cyclopentane-1,3-dicarboxylic acid di-tert-butyl ester (1.19 g). A mixture of 4-(4-chloro-phenyl)-5-(4-nitro-phenyl)-2-oxo-cyclopentane-1,3 20 dicarboxylic acid di-tert-butyl ester (1.0 g, 2.0 mmol) in hydrobromic acid (4.37 mL, 48%) and acetic acid (3.21 mL) was heated at reflux overnight. After cooling to room temperature, water was added. The mixture was washed with diethyl ether and then basified with 10 N NaOH. The aqueous layers were extracted with methylene chloride. The organic extracts were washed with brine, dried over magnesium sulfate and evaporated 25 to give 1-(4-chloro-phenyl)-2-(4-nitro-phenyl)-ethane- 1,2-diamine (464 mg, 80%). To a solution of 1-(4-chloro-phenyl)-2-(4-nitro-phenyl)-ethane-1,2-diamine (200 mg, 0.685 mmol) and ethyl 4-methoxy-benzimidate hydrochloride (148 mg, 0.686 mmol) in ethanol (5 mL) was added triethylamine (0.11 mL, 0.79 mmol). The reaction mixture was heated at reflux for 12 h. The solvent was removed to give a clear oil. It was then 30 taken in methylene chloride (2 mL) and aqueous sodium carbonate. The product was extracted with methylene chloride (2 x 20 mL). The organic layers were washed with brine (1 x 5 mL), dried (Na2SO4) and concentrated. Purification of the crude residue by Biotage WO 03/051359 PCT/EPO2/13904 - 40 flash chromatography eluting with 70% ethyl acetate in hexanes gave 4-(4-chloro-phenyl) 2-(4-methoxy-phenyl)-5-(4-nitro-phenyl)-4,5-dihydro- 1H-imidazole (103 mg, 37%). Isobutyryl chloride (32 pL, 0.30 mmol) was added to a solution of triethylamine (71 pL, 0.51 mmol) and 4-(4-chloro-phenyl)-2-(4-methoxy-phenyl)-5-(4-nitro-phenyl)-4,5 5 dihydro-1H-imidazole (103 mg, 0.25 mmol). The reaction mixture was stirred at room temperature for 2 h and it was then diluted with methylene chloride and aqueous sodium. The organic layer was washed with water and brine, and dried over sodium sulfate. The solvents were remove under reduced pressure and chromatography of the residue over silica gel using 10-40% ethyl acetate in hexanes gave 2 products: 10 a) 1- [5-(4-Chloro-phenyl)-2-(4-methoxy-phenyl)-4-(4-nitro-phenyl)-4,5-dihydro imidazol-1-yl]-2-methyl-propan-l-one (48 mg, 40%). HR-MS (ES, m/z) calculated for C26H25N304CI [(M+H)+] 478.1528, observed 478.1533 0
O
O' 0 C1 ci b) 1- [4-(4-chloro-phenyl)-2-(4-methoxy-phenyl)-5-(4-nitro-phenyl)-4,5-dihydro 15 imidazol-1-yl]-2-methyl-propan-l-one (31 mg, 26%). HR-MS (ES, m/z) calculated for C26H25N304C1 [(M+H)+] 478.1528, observed 478.1533. Example 6 1- [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro-imidazol- 1-yl] 20 2-methyl-propan- 1-one C1/ 10 NC0 SN\b WO 03/051359 PCT/EPO2/13904 -41 A mixture of 2-cyanophenol (5.0 g, 42 mmol), cesium carbonate (27.1 g, 82.9 mmol) and 2-iodopropane (7.63 mL, 76 mmol) in acetone (80 mL) was heated at 60 oC with vigorous stirring. After 45 min, the gray brown mixture was decanted and the acetone layer was concentrated in vacuo. Water was added to dissolve the solid, and the mixture 5 was extracted with diethyl ether (3 x 200 mL). The organic layers were washed with water, 1 N ammonium hydroxide and brine, and dried over anhydrous sodium sulfate. The solids were then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil
T
' 32-63pm, 60 A silica gel) eluting with 5% ethyl acetate in hexanes yielded 2-isopropoxy-benzonitrile (6.6 g, 97%) as 10 a colorless liquid. Hydrogen chloride gas was passed through a solution of 2-isopropoxy-benzonitrile (6.6 g, 40.9 mmol) in anhydrous ethanol (75mL) at 0 oC in a pressure tube. After 30 min, hydrogen chloride gas was stopped. The reaction vessel was sealed and stirred at room temperature for 3 d. The pressure was released only after the tube has been cooled to 0 oC. 15 The solvent was removed to give a pale yellow oil (10.1 g). It was triturated in diethyl ether (100 mL) to afford a white solid. Ethyl 2-isopropoxy-benzimidate hydrochloride (9.17 g, 92%) was collected by filtration, washed with diethyl ether (3 x 25 mL), and dried in vacuo. It was used without further purification. To a solution of triethylamine (0.88 mL, 6.26 mmol) in ethanol (3.5 mL) were added 20 meso-1,2-bis-(4-chloro-phenyl)-ethane-1,2-diamine (0.80 g, 2.85 mmol, prepared according to the procedure described by Vogtle, F.; Goldschmitt, E. Chem. Ber. 1976, 109, 1-40) and ethyl 2-isopropoxy-benzimidate hydrochloride (0.86 g, 3.52 mmol). The reaction mixture was refluxed overnight. After cooled to room temperture, the reaction mixture was diluted with methylene chloride washed with with1 N HCI and 5% aqueous 25 sodium bicarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. Evaporation of the solvents and chromatography of the residue over silica gel using 2% methanol in methylene chloride gave 4,5-bis-(4-chloro-phenyl)-2-(2 isopropoxy-phenyl)-4,5-dihydro- 1H-imidazole (0.86 g, 71%). Isobutyryl chloride (8.1 pL, 0.077 mmol) was added to a solution of triethylamine 30 (10.8 pL, 0.077 mmol) and 4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-phenyl)-4,5 dihydro-1H-imidazole (30 mg, 0.071 mmol) in methylene chloride (3 mL). The reaction mixture was stirred at room temperature for 3 h. It was then diluted with methylene chloride and washed with water and brine, and dried over sodium sulfate. The solvents WO 03/051359 PCT/EP02/13904 - 42 were remove under reduced pressure and chromotagraphy of the residue over silica gel using 25% ethyl acetate in hexanes gave 1- [4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy phenyl)-4,5-dihydro-imidazol-1-yl]-2-methyl-propan-1-one. HR-MS (ES, m/z) calculated for C28H29N202C2 [(M+H)+] 495.1601, observed 495.1606. 5 Example 7 [4,5-Bis- (4-chloro-phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro-imidazol-1-yl] -(4 pyrrolidin-1-yl-piperidin- 1 -yl)-methanone Cl __ O CI 0 CI N 10 Phosgene (2.95 mL, 5.69 mmol, 1.93 M in toluene) was added dropwise to a cooled mixture of triethylamine (1.3 mL, 9.4 mmol) and 4,5-bis-(4-chloro-phenyl)-2-(2 isopropoxy-phenyl)-4,5-dihydro-1H-imidazole (0.80 g, 1.88 mmol, example 6) in methylene chloride (15 mL) at 0 'C. The reaction mixture was stirred for 30 min at 0 oC and evaporated. The residue was kept under high vacuum for 30 min. Chromatography of 15 the residue over silica gel using 60-80% methylene chloride in hexanes gave 4,5-bis-(4 chloro-phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (0.71 g, 77%) 4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro-imidazole-1 carbonyl chloride (200 mg, 0.41 mmol) was added a solution of triethylamine (0.23 mL, 20 1.64 mmol) and 4-(1-pyrrolidinyl)-piperidine (0.11 g, 0.70 mmol) in methylene chloride (8 mL) at 0 oC over 15 min. After 30 min, the reaction was worked up with water. The mixture was extracted with methylene chloride and washed with water and brine. The organic extracts were dried over sodium sulfate and evaporated. Chromatography of the residue over silica gel using 1-2% methanol in methylene chloride gave [4,5-bis-(4-chloro 25 phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro-imidazol-l-yl]-(4-pyrrolidin-1l-yl- WO 03/051359 PCT/EP02/13904 - 43 piperidin-1-yl)-methanone (0.18 g, 72%) as an off-white foam. HR-MS (ES, m/z) calculated for C34H39N402C2 [(M+H)+] 605.2445, observed 605.2448 Example 8 5 In a similar manner as described in examples 6 and 7, the following compounds were prepared. a)[4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro-imidazol-1-yl] piperazin-1-yl-methanone. HR-MS (ES, m/z) calculated for C29H31N402C2 [(M+H)+] 537.1819, observed 537.1828 1 CI 10 10 0J b) [4,5-Bis- (4-chloro-phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro-imidazol- 1 -yl] (4-dimethylamino-piperidin-1l-yl)-methanone. HR-MS (ES, m/z) calculated for C32H37N402C12 [(M+H)+] 579.2288, observed 579.2293. 15 c)[1,4']Bipiperidinyl- l'-yl-[4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-phenyl)-4,5 dihydro-imidazol-1-yl]-methanone. HR-MS (ES, m/z) calculated for C35H41N402C12 [(M+H)+] 619.2601, observed 619.2606. d)[4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro-imidazo l-1-y] [4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone. HR-MS (ES, m/z) calculated for 20 C31H35N403C12 [(M+H)+] 581.2081, observed 581.2082. e){4,5-Bis-(4-chloro-phenyl)-2-[2-(2-methyl-butoxy)-phenyl]-4,5-dihydro imidazol-1-yl}-piperazin-1-yl-methanone. HR-MS (ES, m/z) calculated for C31H35N402C2 [(M+H)+] 565.2132, observed 565.2140.
WO 03/051359 PCT/EP02/13904 - 44 f)[4,5-Bis-(4-chloro-phenyl)-2-(2-pentyloxy-phenyl)-4,5-dihydro-imidazol- 1-yl] piperazin-1-yl-methanone. HR-MS (ES, m/z) calculated for C31H35N402C2 [(M+H)+] 565.2132, observed 565.2138. g)[4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-phenyl)-4,5-dihydro-imidazol- 1-yl] 5 piperazin- 1-yl-methanone, trifluoroacetic acid salt. HR-MS (ES, m/z) calculated for C28H29N402C2 [(M+H)+] 523.1662, observed 523.1666. h)[4,5-Bis-(4-chloro-phenyl)-2-(3-isopropoxy-phenyl)-4,5-dihydro-imidazol- l-y] piperazin-1-yl-methanone, trifluoroacetic acid salt. HR-MS (ES, m/z) calculated for C29H31N402C12 [(M+H)+] 537.1819, observed 537.1824. 10 i) 1- {4- [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-phenyl)-4,5-dihydro-imidazole- 1 carbonyl]-piperazin-1-yl}-ethanone. HR-MS (ES, m/z) calculated for C30H31N403Br2 [(M+H)+] 653.0758, observed 653.0771. j)[4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-phenyl)-4,5-dihydro-imidazol- 1-yl]-[4 (2-hydroxy-ethyl)-piperazin- l-yl]-methanone. HR-MS (ES, m/z) calculated for 15 C30H33N403Br2 [(M+H)+] 655.0914, observed 655.0928. k)1- {4-[4,5-Bis-(4-bromo-phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro-imidazole 1-carbonyl]-piperazin-1-yl}-ethanone. HR-MS (ES, m/z) calculated for C31H33N403Br2 [(M+H)+] 667.0914, observed 667.0920. 1)[4,5-Bis-(4-bromo-phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro-imidazol- 1-yl] 20 [4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone. HR-MS (ES, m/z) calculated for C31H35N403Br2 [(M+H)+] 669.1071, observed 669.1069. Example 9 [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro 25 imidazol- 1 -yl]-[4-(2-hydroxy-ethyl)-piperazin- l-yl]-methanone hydrochloride WO 03/051359 PCT/EP02/13904 - 45 10 C/ C11 N >=I NJ o A mixture of 2-hydroxy-4-methoxybenzaldehyde (25.0 g, 164 mmol), sodium acetate (26.4 g, 322 mmol), nitroethane (23 g, 307 mmol) in acetic acid (45 mL) was heated at reflux for 6 h. The mixture was then cooled to room temperature and poured onto ice 5 water. The solids were filtered off, washed with water and dried. Recrystallization of the crude solid in ethyl acetate gave 2-hydroxy-4-methoxy-benzonitrile as a brown solid (15.9 g, 65%). Cesium carbonate (51.5 g, 158 mmol) was added to a solution of 2-hydroxy-4 methoxybenzonitrile (11.8 g, 79 mmol) in acetone (100 mL). 2-lodopropane (12.5 mL, 10 125 mmol) was added. The mixture was heated at reflux for 3 h. Water was added and the mixture was extracted with diethyl ether (4 x 100 mL). The combined organic extracts were washed with diluted ammonium hydroxide, brine and dried (MgSO4). Evaporation of the solvents and chromatography of the residue over silica gel using 5% diethyl ether in hexanes gave 2-isopropoxy-4-methoxybenzonitrile (13.2 g, 87%). 15 Hydrogen chloride gas was passed through a solution of 2-isopropoxy-4 methoxybenzonitrile (13.2 g, 69 mmol) in absolute ethanol (200 mL) in a pressure tube for 1 h at -10 oC. The tube was sealed and stirred at room temperature for 7 d. The tube was cooled to -10 oC and more ethanol (100 mL) was added. Hydrogen chloride gas was passed through it for additional 30 min at -10 oC. The tube was resealed and stirred at room 20 temperature for 7 d. Evaporation of the solvents and trituration of the residue in diethyl ether gave ethyl 2-isopropoxy-4-methoxy-benzimidate hydrochloride as a white solid (17.5 g, 99%). It was used without further purification. A mixture of ethyl 2-isopropoxy-4-methoxy-benzimidate hydrochloride (8.21 g, 30 mmol), meso-1,2-bis-(4-chloro-phenyl)-ethane-1,2-diamine (7.59 g, 27 mmol, prepared 25 according to the procedure described by Vogtle, F.; Goldschmitt, E. Chem. Ber. 1976, 109, 1-40) and triethylamine (8.35 mL, 60 mmol) in ethanol (200 mL) was heated at reflux for 24 h. Additional ethyl 2-isopropoxy-4-methoxy-benzimidate hydrochloride (1.64 g, 6 WO 03/051359 PCT/EP02/13904 - 46 mmol) was added and the reaction mixture was heated at reflux for another 24 h. Aqueous sodium bicarbonate was added and it was extracted with methylene chloride (3 x). The combined organic extracts were washed with water and brine, and dried over sodium sulfate. Chromatography of the residue over silica gel using 0.5-2% methanol in methylene 5 chloride followed by recrystallization using diethyl ether in pentane gave 4,5-bis-(4-chloro phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (9 g, 73%). Phosgene (12 mL, 23 mmol, 1.93 M in toluene) was added dropwise to a mixture of triethylamine (3.75 mL, 26.9 mmol) and 4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4 methoxy-phenyl)-4,5-dihydro-1H-imidazole (3.50 g, 7.69 mmol) in methylene chloride 10 (80 mL) at 0 oC. The reaction mixture was stirred for 30 min at 0 oC and evaporated. The residue was kept under high vacuum for 30 min. Methylene chloride (50 mL) was added to the residue and the solution was added dropwise to a solution of 2-piperazin-1-yl ethanol (10 g) in methylene chloride (200 mL) at 0 'C over 15 min. After 30 min, the reaction was worked up with water. The mixture was extracted with methylene chloride 15 and washed with water and brine. The organic extracts were dried over sodium sulfate and evaporated. Chromatography of the residue over silica gel using 1-2% methanol in methylene chloride gave [4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl) 4,5-dihydro-imidazol- 1-yl]- [4-(2-hydroxy-ethyl)-piperazin- 1-yl] -methanone as a light yellow foam (4.07 g, 87%). 20 [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- l-yl]-[4-(2-hydroxy-ethyl)-piperazin- l-yl]-methanone (2.20 g, 3.60 mmol) was dissolved in dilute hydrochloric acid (0.23 N, 20 mL). The light yellow solution was filtered and lyophilized to give [4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy phenyl)-4,5-dihydro-imidazol- 1-yl]-[4-(2-hydroxy-ethyl)-piperazin- 1-yl]-methanone 25 hydrochloride as a off-white powder (2.26 g, 97%). HR-MS (ES, m/z) calculated for C32H37N404C12 [(M+H)+] 611.2187, observed 611.2195. Example 10 In a similar manner as described in example 9, the following compounds were 30 prepared.
WO 03/051359 PCT/EP02/13904 - 47 a) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl] - (4-methanesulfonyl-piperazin-1-yl)-methanone. HR-MS (ES, m/z) calculated for C30H33N405SC12 [(M+H)+] 631.1543, observed 631.1549 CI N , No \ -0 0 O'SNO ~ < rN 5 b)[4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl]-[4-(2-hydroxy-ethyl)-piperazin-1l-yl]-methanone. HR-MS (ES, m/z) calculated for C31H35N404C2 [(M+H)+] 597.2030, observed 597.2038. c) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-l-yl]-morpholin-4-yl-methanone. HR-MS (m/z) calculated for C29H30N304C12 10 [(M+H)+] 554.1608, observed 554.1614 d)[4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1l-yl]-(4-methyl-piperazin-1l-yl)-methanone. HR-MS (ES, m/z) calculated for C30H33N403C12 [(M+H)+] 567.1924, observed 567.1929. e)1- {4-[4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro 15 imidazole-l1-carbonyl]-piperazin-1l-yll-ethanone. HR-MS (ES, m/z) calculated for C31H33N404C2 [(M+H)+] 595.1874, observed 595.1882. f)4-[4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazole- 1 -carbonyl]-piperazin-2-one. HR-MS (ES, m/z) calculated for C29H29N404CI2 [(M+H)+] 567.1561, observed 567.1571. 20 g)[4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-piperazin- 1-yl-methanone. HR-MS (ES, m/z) calculated for C30H33N403C12 [(M+H)+] 567.1924, observed 567.1927.
WO 03/051359 PCT/EP02/13904 - 48 h) 1- {4- [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 dihydro-imidazole- 1-carbonyl]-piperazin-1-yl}-ethanone. HR-MS (ES, m/z) calculated for C32H35N404C2 [(M+H)+] 609.2030, observed 609.2036. i)[4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro 5 imidazol-1-yl] -(4-methanesulfonyl-piperazin-1-yl)-methanone was prepared by sulfonylation of [4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 dihydro-imidazol-1-yl]-piperazin-1-yl-methanone (example 10 g). HR-MS (ES, m/z) calculated for C31H35N405SC12 [(M+H)+] 645.1700, observed 645.1710. j)[4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro 10 imidazol-1-yl]-(2,5-dimethyl-piperazin-1-yl)-methanone. HR-MS (ES, m/z) calculated for C32H37N403C2 [(M+H)+] 595.2237, observed 595.2240. k)4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazole-1-carboxylic acid bis-(2-hydroxy-ethyl)-amide. HR-MS (ES, m/z) calculated for C30H34N305C2 [(M+H)+] 586.1870, observed 586.1878. 15 1)[4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1l-yl]-(4-ethyl-piperazin-1-yl)-methanone. HR-MS (ES, m/z) calculated for C32H37N403C2 [(M+H)+] 595.2237, observed 595.2241. m) [1,4']Bipiperidinyl- 1'-yl-[4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy phenyl)-4,5-dihydro-imidazol-1l-yl]-methanone. HR-MS (ES, m/z) calculated for 20 C36H43N403C2 [(M+H)+] 649.2707, observed 649.2712. n) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone. HR-MS (ES, m/z) calculated for C35H41N403C2 [(M+H)+] 635.2550, observed 635.2559. o) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro 25 imidazol-l-yl]-(4-dimethylamino-piperidin-1-yl)-methanone. HR-MS (ES, m/z) calculated for C33H39N403C2 [(M+H)+] 609.2394, observed 609.2395. p)[4,5-Bis-(4-chloro-phenyl)-2- (2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-morpholin-4-yl-methanone. HR-MS (ES, m/z) calculated for C30H32N304C2 [(M+H)+] 568.1765, observed 568.1768.
WO 03/051359 PCT/EP02/13904 - 49 q) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1l-yl]-(4-isopropyl-piperazin-1-yl)-methanone. HR-MS (ES, m/z) calculated for C33H39N403C2 [(M+H)+] 609.2394, observed 609.2395. The N-isopropyl piperazine used in the synthesis of above compound was prepared according to the procedure 5 described in Renau, Thomas E.; Sanchez, Joseph P. et al. J. Med. Chem. 1996, 39, 729-35. r)4- [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazole- 1-carbonyl]-piperazin-2-one. HR-MS (ES, m/z) calculated for C30H31N404C12 [(M+H)+] 581.1717, observed 581.1723. s)[4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro 10 imidazol-1l-y]-(4-hydroxymethyl-piperidin-l-yl)-methanone. HR-MS (ES, m/z) calculated for C32H36N304CI2 [(M+H)+] 596.2078, observed 596.2081. t)[4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-[4-(2-hydroxy-ethyl)-piperidin- 1 -yl] -methanone. HR-MS (ES, m/z) calculated for C33H38N304CI2 [(M+H)+] 610.2234, observed 610.2236. 15 u) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl]-(3-methyl-piperazin-1-yl)-methanone. HR-MS (ES, m/z) calculated for C31H35N403C2 [(M+H)+] 581.2081, observed 581.2081. v)1- {4- [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 dihydro-imidazole-1-carbonyl]-2-methyl-piperazin-1l-yl}-ethanone. HR-MS (ES, m/z) 20 calculated for C33H37N404C12 [(M+H)+] 623.2187, observed 623.2190. w)[4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl]-(4-methanesulfonyl-3-methyl-piperazin-1-yl)-methanone was prepared by sulfonylation of [4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 dihydro-imidazol-1-yl]-(3-methyl-piperazin-1-yl)-methanone (example 10u). HR-MS 25 (ES, m/z) calculated for C32H37N405SC12 [(M+H)+] 659.1856, observed 659.1856. x) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl]-(4-hydroxy-piperidin-1-yl)-methanone. HR-MS (ES, m/z) calculated for C31H34N304C2 [(M+H)+] 582.1921, observed 582.1926.
WO 03/051359 PCT/EP02/13904 - 50 y)(4-Aminomethyl-piperidin- 1-yl)-[4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4 methoxy-phenyl)-4,5-dihydro-imidazol-1l-yl]-methanone. HR-MS (ES, m/z) calculated for C32H37N403C2 [(M+H)+] 595.2237, observed 595.2243. z) [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro 5 imidazol- 1-yl]-[4-(2-hydroxy-ethyl)-piperazin-1-yl] -methanone. HR-MS (ES, m/z) calculated for C31H35N404Br2 [(M+H)+] 685.1020, observed 685.1031. aa) [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1l-yl]-piperazin-1-yl-methanone. HR-MS (ES, m/z) calculated for C29H31N403Br2 [(M+H)+] 641.0758, observed 641.0762. 10 bb)[4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone was prepared by sulfonylation of [4,5-bis-(4-bromo-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl]-piperazin-1-yl-methanone (example 10 aa) using the method known in the art. HR-MS (ES, m/z) calculated for C30H33N405SBr2 [(M+H)+] 719.0533, observed 15 719.0540. cc)1-{4-[4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazole- 1-carbonyl]-piperazin-1-yl}-ethanone. HR-MS (ES, m/z) calculated for C31H33N404Br2 [(M+H)+] 683.0863, observed 683.0866. dd)[4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro 20 imidazol-1l-yl]-(4-methyl-piperazin-1-yl)-methanone. HR-MS (ES, m/z) calculated for C30H33N403Br2 [(M+H)+] 655.0914, observed 655.0917. ee)4-[4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazole- 1-carbonyl]-piperazine- 1-carbaldehyde. HR-MS (ES, m/z) calculated for C30H31N404Br2 [(M+H)+] 669.0707, observed 669.0713. 25 ff)[4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone. HR-MS (ES, m/z) calculated for C34H39N403Br2 [(M+H)+] 709.1384, observed 709.1401. gg)[4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl]-(4-dimethylamino-piperidin-1-yl)-methanone. HR-MS (ES, m/z) 30 calculated for C32H37N403Br2 [(M+H)+] 683.1227, observed 683.1250.
WO 03/051359 PCT/EP02/13904 -51 hh) [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1l-yl]-(4-isopropyl-piperazin-1-yl)-methanone. HR-MS (ES, m/z) calculated for C32H37N403Br2 [(M+H)+] 683.1227, observed 683.1231. ii)4-[4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro 5 imidazole-1-carbonyl]-piperazin-2-one. HR-MS (ES, m/z) calculated for C29H29N404Br2 [(M+H)+] 655.0550, observed 655.0557. jj)[4,5-Bis-(4-bromo-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1 -yl] -piperazin-1 -yl-methanone. HR-MS (ES, m/z) calculated for C30H33N403Br2 [(M+H)+] 655.0914, observed 655.0918 10 kk)1-{4-[4,5-Bis-(4-bromo-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 dihydro-imidazole-l1-carbonyl]-piperazin-1l-yl}-ethanone. HR-MS (ES, m/z) calculated for C32H35N404Br2 [(M+H)+] 697.1020 observed 697.1028. 11)[4,5-Bis-(4-bromo-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl] -(4-methanesulfonyl-piperazin-1-yl)-methanone was prepared by 15 sulfonylation of [4,5-bis-(4-bromo-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 dihydro-imidazol-1-yl]-piperazin-l-yl-methanone (example 10 jj) using the method known in the art. HR-MS (ES, m/z) calculated for C31H35N405SBr2 [(M+H)+] 733.0690, observed 733.0696. mm) [4,5-Bis-(4-bromo-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro 20 imidazol-1l-yl]-(4-methyl-piperazin-1-yl)-methanone. HR-MS (ES, m/z) calculated for C31H35N403Br2 [(M+H)+] 669.1071, observed 669.1078. nn)[4,5-Bis-(4-bromo-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl]-morpholin-4-yl-methanone. HR-MS (ES, m/z) calculated for C30H32N304Br2 [(M+H)+] 656.0754, observed 656.0762. 25 oo)[1,4']Bipiperidinyl- l'-yl-[4,5-bis-(4-bromo-phenyl)-2-(2-isopropoxy-4 methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-methanone. HR-MS (ES, m/z) calculated for C36H43N403Br2 [(M+H)+] 737.1697, observed 737.1707. pp) [4,5-Bis-(4-bromo-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl]-(4-ethyl-piperazin-1l-yl)-methanone. HR-MS (ES, m/z) calculated for 30 C32H37N403Br2 [(M+H)+] 683.1227, observed 683.1232.
WO 03/051359 PCT/EPO2/13904 - 52 qq)4- [4,5-Bis-(4-bromo-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazole-1-carbonyl]-piperazin-2-one. HR-MS (ES, m/z) calculated for C30H31N404Br2 [(M+H)+] 669.0707, observed 669.0718. rr) [4,5-Bis-(4-cyano-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro 5 imidazol-1-yl]-piperazin-1-yl-methanone. HR-MS (ES, m/z) calculated for C32H33N603 [(M+H)+] 549.2609, observed 549.2614 ss) 1-(4-{4,5-Bis-(4-chloro-phenyl)-2-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl] 4,5-dihydro-imidazole- 1-carbonyl}-piperazin-1-yl)-ethanone. HR-MS (ES, m/z) calculated for C32H35N405C12 [(M+H)+] 625.1979, observed 625.1987. 10 tt) 1-(4-{4,5-Bis-(4-chloro-phenyl)-2-[2-(2-fluoro-ethoxy)-4-methoxy-phenyl]-4,5 dihydro-imidazole- 1-carbonyl}-piperazin-1-yl)-ethanone. HR-MS (ES, m/z) calculated for C31H32N404FC12 [(M+H)+] 613.1779, observed 613.1775. uu)4- {4,5-Bis-(4-chloro-phenyl)-2-[2-(2-fluoro-ethoxy)-4-methoxy-phenyl]-4,5 dihydro-imidazole-1-carbonyl}-piperazin-2-one. HR-MS (ES, m/z) calculated for 15 C29H28N404FC12 [(M+H)+] 585.1466, observed 585.1475. Example 11 In a similar manner as described in example 9, the following compounds were prepared. 20 a) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl]-piperazin-1-yl-methanone hydrochloride. HR-MS (ES, m/z) calculated for C29H31N403Cl2 [(M+H)+] 553.1768, observed 553.1773 CI 10 \00 N N N C 0< 0 WO 03/051359 PCT/EP02/13904 - 53 b)4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazole-1-carboxylic acid methyl-(2-methylamino-ethyl)-amide, trifluoroacetic acid salt. HR-MS (ES, m/z) calculated for C29H33N403C2 [(M+H)+] 555.1924, observed 555.1929. 5 c)4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazole-1-carboxylic acid (2-dimethylamino-ethyl)-methyl-amide, trifluoroacetic acid salt. HR-MS (ES, m/z) calculated for C30H35N403C2 [(M+H)+] 569.2081, observed 569.2085. d)4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro 10 imidazole-1-carboxylic acid (2-dimethylamino-ethyl)-amide, trifluoroacetic acid salt. HR MS (ES, m/z) calculated for C29H33N403C12 [(M+H)+] 555.1924, observed 555.1940. e)4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazole-l1-carboxylic acid (2-amino-ethyl)-amide, trifluoroacetic acid salt. HR-MS (m/z) calculated for C27H29N403C2 [(M+H)+] 527.1611, observed 527.1621. 15 f) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol 1-yl] -(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone hydrochloride. HR-MS (ES, m/z) calculated for C34H39N403C12 [(M+H)+] 621.2394, observed 621.2400. g) [4,5-Bis-(4-chloro-phenyl)-2-(4-methoxy-2-propoxy-phenyl)-4,5-dihydro imidazol-1-yl]-piperazin-1-yl-methanone, trifluoroacetic acid salt. HR-MS (ES, m/z) 20 calculated for C30H33N403C2 [(M+H)+] 567.1924, observed 567.1932. h)[4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl] - (4-methyl-piperazin- 1 -yl)-methanone hydrochloride. HR-MS (ES, m/z) calculated for C31H35N403C12 [(M+H)+] 581.2081, observed 581.2086. i)4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro 25 imidazole-1-carboxylic acid (2-morpholin-4-yl-ethyl)-amide hydrochloride. HR-MS (ES, m/z) calculated for C32H37N404C2 [(M+H)+] 611.2187, observed 611.2197. j)4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazole-l1-carboxylic acid (2-piperazin- l-yl-ethyl)-amide hydrochloride. HR-MS (ES, m/z) calculated for C32H38N503C2 [(M+H)+] 610.2346, observed 610.2348.
WO 03/051359 PCT/EP02/13904 - 54 k) [4,5-Bis-(4-chloro-phenyl)-2-(2-isobutoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl]-piperazin-1-yl-methanone hydrochloride. HR-MS (ES, m/z) calculated for C31H35N403C2 [(M+H)+] 581.2081, observed 581.2081. 1) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro 5 imidazol-1-yl]-(3-methyl-piperazin-1l-yl)-methanone hydrochloride. HR-MS (ES, m/z) calculated for C31H35N403C2 [(M+H)+] 581.2081, observed 581.2084. m) {4,5-Bis-(4-chloro-phenyl)-2-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl] -4,5 dihydro-imidazol-1l-yl}-piperazin-1-yl-methanone, trifluoroacetic acid salt. HR-MS (ES, m/z) calculated for C30H33N404C12 [(M+H)+] 583.1874, observed 583.1875. o10 n) {4,5-Bis-(4-chloro-phenyl)-2- [2-(2-fluoro-ethoxy)-4-methoxy-phenyl]-4,5 dihydro-imidazol-1-yl}-piperazin-1-yl-methanone. HR-MS (ES, m/z) calculated for C29H30N403FC2 [(M+H)+] 571.1674, observed 571.1676. o) {4,5-Bis-(4-chloro-phenyl)-2-[2-(2-fluoro-ethoxy)-4-methoxy-phenyl]-4,5 dihydro-imidazol- l-yl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone hydrochloride. 15 HR-MS (ES, m/z) calculated for C34H38N403FC12 [(M+H)+] 639.2300, observed 639.2303. Example 12 2-Amino-1- {4-[4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 20 dihydro-imidazole-l1-carbonyl]-piperazin-1l-yl}-ethanone N 0 0 >~No CI [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl]-piperazin-1-yl-methanone (52 mg, 0.092 mmol, example 10) was added to a solution of N-(t-butoxycarbonyl)glycine (21 mg, 0.119 mmol) in THF (12 mL), followed WO 03/051359 PCT/EPO2/13904 - 55 by diisopropyl carbodiimide (19.7 iL, 0.125 mmol). After 3 h, the reaction mixture was concentrated and diluted with methylene chloride. The mixture was washed with aqueous sodium carbonate, water and brine, and dried over sodium sulfate. Evaporation of the solvents and chromatography of the residue over silica using 1-2 % methanol in methylene 5 chloride gave (2-{4-[4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 dihydro-imidazole-l1-carbonyl]-piperazin- l-yl}-2-oxo-ethyl)-carbamic acid tert-butyl ester (54 mg, 81%). Trifluoroacetic acid (2 mL, 26 mmol) was added to a solution of (2-{4- [4,5-bis-(4 chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole- 1-carbonyl] 10 piperazin-1-yl}-2-oxo-ethyl)-carbamic acid tert-butyl ester (40 mg, 0.054 mmol) in methylene chloride (6 mL). The reaction mixture was stirred for 2.5 h and diluted with methylene chloride. The mixture was washed aqueous sodium carbonate, water and brine, and dried over sodium sulfate. Evaporation of the solvents and chromatography of the residue over silica gel with 5-10% methanol in methylene chloride gave 2-amino-1-{4-[4,5 15 bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole- 1 carbonyl]-piperazin-1-yl}-ethanone (22 mg, 65%). HR-MS (ES, m/z) calculated for C32H36N504C2 [(M+H)+] 624.2139, observed 624.2147. Example 13 20 In a similar manner as described in example 12, the following compounds were prepared. a) 1- {4-[4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 dihydro-imidazole-l1-carbonyl]-piperazin-1-yl}-2-hydroxy-ethanone. HR-MS (ES, m/z) calculated for C32H35N405C12 [(M+H)+] 625.1979, observed 625.1984 c1 10 N I 0 N. 25=O o1 25 0 WO 03/051359 PCT/EPO2/13904 -56 b) 1- {4- [4,5-Bis- (4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 dihydro-imidazole- 1-carbonyl]-piperazin- 1-yl}-2,3-dihydroxy-propan- 1-one. HR-MS (ES, m/z) calculated for C33H37N406C2 [(M+H)+] 655.2085, observed 655.2090. 5 Example 14 [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl] - [4-(2,3-dihydroxy-propyl)-piperazin-1-yl]-methanone cl 10
N
0 O . N CI N [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro 10 imidazol-1-yl]-piperazin-1-yl-methanone (50 mg, 0.088 mmol, example 10 g) was dissolved in anhydrous methanol (10 mL). Glycidol (0.15 mL, 2.26 mmol) was added and the reaction was heated at 40 'C for 20 h. The mixture was cooled to room temperature and concentrated in vacuo. Chromatography of the residue over silica gel using 1-6% methanol in methylene chloride gave [4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4 15 methoxy-phenyl)-4,5-dihydro-imidazol-1l-yl]- [4-(2,3-dihydroxy-propyl)-piperazin-1-yl] methanone (25 mg, 44%). HR-MS (ES, m/z) calculated for C33H39N405C2 [(M+H)+] 641.2292, observed 641.2300. Example 15 20 4-[4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazole- 1-carbonyl]-piperazine- 1-carboxylic acid dimethylamide WO 03/051359 PCT/EP02/13904 - 57 C1 0 N. 0 ' N \=O N
CI
N 0
N
I Phosgene (0.26 mL, 0.5 mmol, 1.93 M in toluene) was added to a solution of 4,5-bis (4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol- 1-yl] piperazin-1-yl-methanone (60 mg, 0.1 1mmol, example 10 g) and triethylamine (97 piL, 5 0.70 mmol) in methylene chloride (10 mL). The reaction mixture was stirred for 1 h. The solvents were evaporated and the residue was dried under high vacuum for 30 min. The residue was redissolved in methylene chloride (10 mL). Dimethylamine (0.993 mL, 1.986 mmol, 2 M in THF) was added and the reaction mixture was stirred overnight. The mixture was washed with brine and the aqueous layer was extracted with methylene 10 chloride. The combined organic extracts were dried (MgSO4) and evaporated. Purification of the residue using reversed phase HPLC gave 4-[4,5-bis-(4-chloro-phenyl) 2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole- 1 -carbonyl] -piperazine- 1 carboxylic acid dimethylamide (48 mg, 68%). HR-MS (ES, m/z) calculated for C33H38N504C12 [(M+H)+] 638.2296, observed 638.2299. 15 Example 16 4-[4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazole- 1-carbonyl]-piperazine- 1-carboxylic acid amide 20O 0 r N C1 0 N 20
N
WO 03/051359 PCT/EP02/13904 - 58 The named compound was prepared in a similar manner as described in example 15. HR-MS (m/z) calculated for C31H34N504C2 [(M+H)+] 610.1983, observed 610.1985. Example 17 5 [4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-phenyl)-4,5-dihydro-imidazol- 1-yl] piperazin- 1-yl-methanone trifluoroacetate salt C I 0 ~F C I, N F 0 CND5 A mixture of 2,4-diethoxybenzaldehyde (5.0 g, 25.7 mmol), sodium acetate (4.23 g, 51.6 mmol), nitroethane (3.86 g, 51.4 mmol) in acetic acid (7 mL) was heated at reflux for 10 6 h. The mixture was then cooled and poured onto ice-water. The solids were filtered off, washed with water and dried. Chromatography of the residue over silica gel using 2-5% ethyl acetate in hexanes followed recrystallization in ethyl acetate gave 2, 4 diethoxybenzonitrile (1.86 g, 38%). Hydrogen chloride gas was passed through a solution of 2,4-diethoxybenzonitrile 15 (1.86 g, 9.7 mmol) in absolute ethanol (20 mL) in a pressure tube for 1 h at -10 oC. The tube was sealed and stirred at room temperature for 12 d. Evaporation of the solvents and trituration of the residue in diethyl ether gave ethyl 2, 4-diethoxy-benzimidate hydrochloride (2.53 g, 95%). A mixture of ethyl 2, 4-diethoxy-benzimidate hydrochloride (0.76 g, 2.79 mmol), 20 meso-1,2-bis-(4-chloro-phenyl)-ethane-1,2-diamine (0.65 mg, 2.327 mmol, prepared according to the procedure described by Vogtle, F.; Goldschmitt, E. Chem. Ber. 1976, 109, 1-40) and triethylamine (0.489 mL, 3.49 mmol) in ethanol (10 mL) was heated at reflux for 4 h. The solvent was removed to give a yellow paste. Aqueous sodium bicarbonate was added and it was extracted with methylene chloride. The combined organic extracts were 25 washed with water and brine, and dried over sodium sulfate. Chromatography of the residue over silica gel with 70% ethyl acetate-hexane gave 4,5-bis-(4-chloro-phenyl)-2 (2,4-diethoxy-phenyl)-4,5-dihydro- 1H-imidazole (0.50 g, 47%).
WO 03/051359 PCT/EPO2/13904 - 59 Phosgene (0.558 mL, 1.1 mmol, 1.93 M in toluene) was added dropwise to a mixture of triethylamine (0.216 mL, 1.54 mmol) and 4,5-bis-(4-chloro-phenyl)-2-(2,4-diethoxy phenyl)-4,5-dihydro-1H-imidazole (0.10 g, 0.22 mmol) in methylene chloride (10 mL) at 0 oC. The reaction mixture was stirred for 1 h at 0 oC and evaporated. The residue was kept 5 under high vacuum for 30 min. Methylene chloride (5 mL) was added to the residue and the solution was added dropwise to a solution of piperazine (0. 38 g, 4.4 mmol) in methylene chloride (5 mL) at 0 oC over 15 min. After 1 h, the reaction was worked up with aqueous sodium bicarbonate. The mixture was extracted with methylene chloride and washed with water and brine. The organic extracts were dried over sodium sulfate and 10 evaporated. Purification using HPLC gave [4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy phenyl)-4,5-dihydro-imidazol-1 -yl]-piperazin- 1-yl-methanone, trifluoroacetic acid salt (4.07 g, 87%). HR-MS (ES, m/z) calculated for C30H33N403C2 [(M+H)+] 567.1924, observed 567.1928. 15 Example 18 In a similar manner as described in example 17 the following compounds were prepared. a)[4,5-Bis- (4-chloro-phenyl)-2-(2,4-diethoxy-phenyl)-4,5-dihydro-imidazol l-1-yl] morpholin-4-yl-methanone. HR-MS (ES, m/z) calculated for C30H32N304C12 20 [(M+H)+] 568.1765, observed 568.1766 1 0 \ o b) [4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-phenyl)-4,5-dihydro-imidazol- 1-yl ] [4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone. HR-MS (ES, m/z) calculated for C32H37N404C2 [(M+H)+] 611.2187, observed 611.2203. 25 c) [4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-phenyl)-4,5-dihydro-imidazol-1-yl] (4-methyl-piperazin-1l-yl)-methanone. HR-MS (ES, m/z) calculated for C31H35N403C12 [(M+H)+] 581.2081, observed 581.2087.
WO 03/051359 PCT/EP02/13904 - 60 d) 1- {4-[4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-phenyl)-4,5-dihydro-imidazole 1-carbonyll]-piperazin-1-yl}-ethanone. HR-MS (ES, m/z) calculated for C32H35N404C12 [(M+H)+] 609.2030, observed 609.2035. e)[4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-phenyl)-4,5-dihydro-imidazol- 1-yl] 5 (4-methanesulfonyl-piperazin-1-yl)-methanone was prepared by sulfonylation of [4,5-bis (4-chloro-phenyl)-2-(2,4-diethoxy-phenyl)-4,5-dihydro-imidazol- 1-yl]-piperazin-1-yl methanone (examplel7). HR-MS (ES, m/z) calculated for C31H35N405SC2 [(M+H)+] 645.1700, observed 645.1704. f)[4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-phenyl)-4,5-dihydro-imidazol- 1l-yl] 10 (4-pyrrolidin-1-yl-piperidin-1l-yl)-methanone. HR-MS (ES, m/z) calculated for C35H41N403C12 [(M+H)+] 635.2550, observed 635.2561. g)[4,5-Bis-(4-bromo-phenyl)-2-(2,4-diethoxy-phenyl)-4,5-dihydro-imidazol-1-yl] (4-methyl-piperazin-1-yl)-methanone. HR-MS (ES, m/z) calculated for C31H35N403Br2 [(M+H)+] 669.1071, observed 669.1074. 15 h) [4,5-Bis-(4-bromo-phenyl)-2- (2,4-diethoxy-phenyl)-4,5-dihydro-imidazol-1-yl] (4-ethyl-piperazin-1-yl)-methanone. HR-MS (ES, m/z) calculated for C32H37N403Br2 [(M+H)+] 683.1227, observed 683.1228. i)[4,5-Bis-(4-bromo-phenyl)-2-(2,4-diethoxy-phenyl)-4,5-dihydro-imidazol- 1-yl] morpholin-4-yl-methanone. HR-MS (ES, m/z) calculated for C30H32N304Br2 20 [(M+H)+] 656.0754, observed 656.0760. Example 19 In a similar manner as described in example 15, the following compounds were prepared from [4,5-bis-(4-chloro-phenyl)-2-(2,4-diethoxy-phenyl)-4,5-dihydro-imidazol 25 1-yl]-piperazin-1-yl-methanone (example 17). a)4-[4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-phenyl)-4,5-dihydro-imidazole- 1 carbonyl]-piperazine-1-carboxylic acid amide. HR-MS (ES, m/z) calculated for C31H34N504C12 [(M+H)+] 610.1983, observed 610.1983 WO 03/051359 PCT/EP02/13904 -61 CI 10 N t" N 7 0 CI5 N b) 4-[4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-phenyl)-4,5-dihydro-imidazole- 1 carbonyl]-piperazine-1-carboxylic acid dimethylamide. HR-MS (ES, m/z) calculated for C33H38N504C12 [(M+H)+] 638.2296, observed 638.2297. 5 Example 20 [4,5-Bis-(4-chloro-phenyl)-2-(4-dimethylamino-2-ethoxy-phenyl)-4,5-dihydro imidazol-1l-yl]-piperazin- 1-yl-methanone Cl N -~ N l=o I0 Cl N 10 Iodine (6.35 g, 25 mmol) in methylene chloride (300 mL) was added dropwise over 3 h to a stirred suspension of thallium(I) acetate (7.90 g, 30 mmol) and 3 dimethylaminophenol (3.43 g, 25 mmol) in methylene chloride (300 mL). The resulting mixture was stirred at room temperature for 24 h and filtered. Evaporation of the solvents and chromatography of the residue over silica gel using 0-5% diethyl ether in hexanes gave 15 5-dimethylamino-2-iodophenol (2.35 g, 36%). A mixture of 5-dimethylaminol-2-iodophenol (0.90 g, 3.42 mmol), cesium carbonate (2.79 g, 8.55 mmol) and iodoethane (0.81 mL, 10 mmol) in acetone (5 mL) was heated at reflux for 2 h. The reaction mixture was cooled to room temperature and water was added. The mixture was extracted with diethyl ether (3 x). The combined organic extracts were 20 washed with brine, dried over magnesium sulfate and evaporated. Chromatography of the residue over silica gel using hexanes gave N, N-dimethyl-2-ethoxy-4-iodo-aniline (0.75 g, 76%).
WO 03/051359 PCT/EPO2/13904 - 62 N, N-dimethyl-2-ethoxy-4-iodo-aniline (0.75 g, 2.58 mmol) was dissolved in DMF (4 mL). Zinc cyanide (0.18 g, 1.54 mmol) was added. Argon was passed through the mixture for 10 min. Tetrakis(triphenylphosphine)palladium (148 mg, 0.13 mmol) was added and the mixture was heated at 110 'C for 24 h. The reaction mixture was cooled and 5 poured into water. The mixture was extracted with ethyl acetate, washed with brine and dried over magnesium sulfate. Evaporation of the solvents and chromatography of the residue over silica gel using 20% ethyl acetate in hexanes gave N, N-dimethyl-2-ethoxy-4 cyano-aniline (187 mg, 38%). Hydrogen chloride gas was passed through a solution of N, N-dimethyl-2-ethoxy-4 10 cyano-aniline (0.185 g, 0.97 mmol) in ethanol (5 mL) at 0 'C for 30 min. The pressure tube was sealed and stirred for 2 d at room temperature. The tube was cooled to 0 oC before the pressure was released. Evaporation of the solvents and trituration of the residue in diethyl ether gave ethyl 4-(N,N-dimethylamino)-2-ethoxy-benzimidate hydrochloride as a white powder (0.25 g, 95%). 15 Triethylamine (0.28 mL, 2.0 mmol) was added to a mixture of 4-(N,N dimethylamino)-2-ethoxy-benzimidate hydrochloride (250 mg, 0.92 mmol) and meso-1,2 bis-(4-chloro-phenyl)-ethane-1,2-diamine (190 mg, 0.68 mmol, prepared according to the procedure described by Vogtle, F.; Goldschmitt, E. Chem. Ber. 1976, 109, 1-40) in ethanol (5 mL). The mixture was heated at reflux overnight. The reaction was worked up with 20 aqueous sodium bicarbonate and extracted with methylene chloride. The organic extracts were washed with brine and dried over sodium sulfate. Evaporation of the solvents and chromatography of the residue over silica gel using 10-30% methanol in methylene chloride gave {4- [4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy phenyl}-dimethyl-amine as a white foam (0.18 g, 59%). 25 Phosgene (0.47 mL, 0.91 mmol, 1.93 M in toluene) was added to a stirred solution of {4-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro- 1H-imidazol-2-yl] -3-ethoxy-phenyl}-dimethyl amine (83 mg, 0.18 mmol) and triethylamine (0.14 mL, 1 mmol) in THF (3 mL) at 0 oC over a period of 5 min. The mixture was stirred for 1 h and evaporated. The residue was dissolved in methylene chloride (2 mL) and added dropwise to a stirred solution of 30 piperazine (0.239 g, 2.77mmol) in methylene chloride (2 mL) at room temperature for 1 h. The mixture was diluted with aqueous sodium bicarbonate and extracted with methylene chloride. The organic extracts were washed with brine and dried over sodium sulfate. Evaporation of the solvents and chromatography of the residue over silica gel using 0-10% WO 03/051359 PCT/EP02/13904 - 63 methanol in methylene chloride gave [4,5-bis-(4-chloro-phenyl)-2-(4-dimethylamino-2 ethoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-piperazin-1-yl-methanone as a white foam (68 mg, 66%). HR-MS (ES, m/z) calculated for C30H34N502C12 [(M+H)+] 566.2084, observed 566.2088. 5 Example 21 In a similar manner as described in example 20 the following compounds were prepared. a)[4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-ethyl-phenyl)-4,5-dihydro-imidazol-1 10 yl]-piperazin-1-yl-methanone. HR-MS (ES, m/z) calculated for C30H33N402C12 [(M+H)+] 551.1975, observed 551.1984 N cl N NJ b)[4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methyl-phenyl)-4,5-dihydro-imidazol 1-yl]-piperazin-1-yl-methanone. HR-MS (ES, m/z) calculated for C29H31N402C12 15 [(M+H)+] 537.1819, observed 537.1824. c)[4,5-Bis-(4-chloro-phenyl)-2-(4-ethyl-2-isopropoxy-phenyl)-4,5-dihydro imidazol-1-yl]-piperazin-1-yl-methanone. HR-MS (ES, m/z) calculated for C31H35N402C12 [(M+H)+] 565.2132, observed 565.2135. d) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methyl-phenyl)-4,5-dihydro 20 imidazol- l-yl] -piperazin- 1-yl-methanone. HR-MS (ES, m/z) calculated for C30H33N402C2 [(M+H)+] 551.1975, observed 551.1980. e) 1- {4- [4,5-Bis- (4-chloro-phenyl)-2-(4-dimethylamino-2-ethoxy-phenyl) -4,5 dihydro-imidazole- 1-carbonyl ]-piperazin- 1-yl}-ethanone. HR-MS (ES, m/z) calculated for C32H36N503CI2 [(M+H)+] 608.2190, observed 608.2201.
WO 03/051359 PCT/EP02/13904 - 64 Example 22 In a similar manner as described in example 20, the following compounds were prepared. 5 a) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-5-methyl-phenyl)-4,5-dihydro-imidazol 1-yl]-piperazin-1-yl-methanone, trifluoroacetic acid salt. HR-MS (ES, m/z) calculated for C32H31N402C2 [(M+H)+] 537.1819, observed 537.1826 1 0 N F SF 0 ct, 0- b)[4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-fluoro-phenyl)-4,5-dihydro-imidazol- 1 10 yl]-(4-pyrrolidin-1-yl-piperidin-1l-yl)-methanone. HR-MS (ES, m/z) calculated for C33H36N402C2F [(M+H)+] 609.2194, observed 609.2204. c) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-fluoro-phenyl)-4,5-dihydro-imidazol- 1 yl] -(4-dimethylamino-piperidin- 1 -yl)-methanone. HR-MS (ES, m/z) calculated for C31H34N402C12F [(M+H)+] 583.2038, observed 583.2041. 15 d) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-fluoro-phenyl)-4,5-dihydro-imidazol 1-yl]-piperazin-1-yl-methanone. HR-MS (ES, m/z) calculated for C28H28N402Cl2F [(M+H)+] 541.1568, observed 541.1571. e) [4,5-Bis-(4-chloro-phenyl)-2-(4-fluoro-2-isopropoxy-phenyl)-4,5-dihydro imidazol-1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone. HR-MS (ES, m/z) 20 calculated for C34H38N402FC12 [(M+H)+] 623.2351, observed 623.2360. f)[4,5-Bis-(4-chloro-phenyl)-2-(4-fluoro-2-isopropoxy-phenyl)-4,5-dihydro imidazol-1-yl]-(4-dimethylamino-piperidin-1l-yl)-methanone. HR-MS (ES, m/z) calculated for C32H36N402FC12 [(M+H)+] 597.2194, observed 597.2197.
WO 03/051359 PCT/EPO2/13904 - 65 g)[4,5-Bis-(4-chloro-phenyl)-2-(4-fluoro-2-isopropoxy-phenyl)-4,5-dihydro imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone. HR-MS (ES, m/z) calculated for C30H32N402FC12 [(M+H)+] 569.1881, observed 569.1887. h)[4,5-Bis-(4-chloro-phenyl)-2-(4-fluoro-2-isopropoxy-phenyl)-4,5-dihydro 5 imidazol- 1-yl]-piperazin- 1-yl-methanone. HR-MS (ES, m/z) calculated for C29H30N402FC12 [(M+H)+] 551.1725, observed 551.1726. i) [4,5-Bis-(4-chloro-phenyl)-2-(4-fluoro-2-isopropoxy-phenyl)-4,5-dihydro imidazol-1l-yl]-(4-methanesulfonyl-piperazin-1l-yl)-methanone. HR-MS (ES, m/z) calculated for C30H32N404SFC12 [(M+H)+] 633.1500, observed 633.1506. 10 j)4- [4,5-Bis-(4-chloro-phenyl)-2-(4-fluoro-2-isopropoxy-phenyl)-4,5-dihydro imidazole- 1 -carbonyl]-piperazin-2-one. HR-MS (ES, m/z) calculated for C29H28N403FC12 [(M+H)+] 569.1517, observed 569.1529. k) [4,5-Bis-(4-chloro-phenyl)-2-chroman-8-yl-4,5-dihydro-imidazol- 1-yl] piperazin- 1-yl-methanone was prepared from 8-bromo-chroman (prepared from 2,6 15 dibromo-phenol using the procedure reported by Thomas, G. H. et al. Tetrahedron Lett. 1998, 39, 2219-22). HR-MS (ES, m/z) calculated for C29H29N402C12 [(M+H)+] 535.1662, observed 535.1672. 1)4- [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-fluoro-phenyl)-4,5-dihydro imidazole-1-carbonyl]-piperazin-2-one. HR-MS (ES, m/z) calculated for 20 C28H26N403FBr2 [(M+H)+] 643.0350, observed 643.0349. m) [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-fluoro-phenyl)-4,5-dihydro-imidazol 1-yl]-morpholin-4-yl-methanone. HR-MS (ES, m/z) calculated for C28H27N303FC12 [(M+H)+] 630.0398, observed 630.0414. n) [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-fluoro-phenyl)-4,5-dihydro-imidazol 25 1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone. HR-MS (ES, m/z) calculated for C33H36N402FBr2 [(M+H)+] 697.1184, observed 697.1188. o)[4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-fluoro-phenyl)-4,5-dihydro-imidazol 1-yl]-(4-dimethylamino-piperidin-1-yl)-methanone. HR-MS (ES, m/z) calculated for C31H34N402FBr2 [(M+H)+] 671.1027, observed 671.1036.
WO 03/051359 PCT/EP02/13904 - 66 p) [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-fluoro-phenyl)-4,5-dihydro-imidazol 1-yl]-piperazin-1-yl-methanone. HR-MS (ES, m/z) calculated for C28H28N402FBr2 [(M+H)+] 629.0558, observed 629.0569. 5 Example 23 [4,5-Bis-(4-chloro-phenyl)-2-(2-cyclopentyloxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl]-piperazin-1-yl-methanone clI 0 N\ I~ N -= CI N To a solution of 2-hydroxy-4-methoxy-benzonitrile (90 mg, 0.60 mmol, example 9), 10 cyclopentanol (55 mg, 0.64 mmol) and triphenylphosphine (167 mg, 0.64 mmol) in THF (3 mL) at -78 oC was added diethyl azodicarboxalate (0.16 mL, 0.860 mmol, 85%). The cooling bath was removed and the reaction was allowed to warm up to room temperature over 1.5 h. The reaction mixture was concentrated in vacuo, and purification of the residue by flash chromatography (Biotage system, KP-Sil TM 32-63 pm, 60 A silica gel) 15 eluting with 0-8% diethyl ether in hexanes yielded 2-cyclopentyloxy-4-methoxy benzonitrile as a clear liquid (125 mg, 90%). Hydrogen chloride gas was passed through a solution of 2-cyclopentyloxy-4 methoxy-benzonitrile (0.12 g, 0.55 mmol) in absolute ethanol (15 mL) in a pressure tube for 1 h at 0 oC. The tube was sealed and stirred at room temperature for 3 d. Evaporation 20 of the solvents and trituration of the residue in diethyl ether gave ethyl 2-cyclopentyloxy-4 methoxy -benzimidate hydrochloride (0.17 g, 100%). A mixture of ethyl 2-cyclopentyloxy-4-methoxy -benzimidate hydrochloride (0.16 g, 0.57 mmol), meso- 1,2-bis-(4-chloro-phenyl)-ethane- 1,2-diamine (0.17 g, 0.56 mmol, prepared according to the procedure described by Vogtle, F.; Goldschmitt, E. Chem. Ber. 25 1976, 109, 1-40) in ethanol (2 mL) was heated at reflux for 18 h. The solvent was removed to give a yellow paste. Aqueous sodium bicarbonate was added and it was extracted with WO 03/051359 PCT/EPO2/13904 - 67 methylene chloride. The combined organic extracts were washed with water and brine, and dried over sodium sulfate. Chromatography of the residue over silica gel with 0-5% methanol in methylene chloride gave 4,5-bis-(4-chloro-phenyl)-2-(2-cyclopentyloxy-4 methoxy-phenyl)-4,5-dihydro- 1H-imidazole. 5 Phosgene (0.48 mL, 0.925 mmol, 1.93 M in toluene) was added dropwise to a mixture of triethylamine (0.14 mL, 1.0 mmol) and 4,5-bis-(4-chloro-phenyl)-2-(2 cyclopentyloxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (89 mg, 0.185 mmol) in THF (2 mL) at 0 oC. The reaction mixture was stirred for 1 h at 0 oC and evaporated. The residue was kept under high vacuum for 30 min. Methylene chloride (2 mL) was added to 10 the residue and the solution was added dropwise to a solution of piperazine (0.24 g, 2.78 mmol) in methylene chloride (2 mL) at 0 *C. After 1 h, the reaction was worked up with aqueous sodium bicarbonate. The mixture was extracted with methylene chloride and washed with water and brine. The organic layer was extracted with 0.5 N HCI (2 x 50 mL). The combined aqueous layers were cooled to 0 oC and basified using 2 N NaOH. The 15 mixture was extracted with methylene chloride (3 x 50 mL). The organic extracts were dried over sodium sulfate and evaporated. Flash chromatography of the residue over silica gel using 3-6 % methanol in methylene chloride gave [4,5-Bis-(4-chloro-phenyl)-2-(2 cyclopentyloxy-4-methoxy-phenyl)-4,5-dihydro-imidazol- 1 -yl]-piperazin-1-yl-methanone (89 mg, 81%). HR-MS (ES, m/z) calculated for C32H35N403C12 [(M+H)+] 593.2081, 20 observed 593.2084. Example 24 In a similar manner as described in example 23 and example 9, the following compounds were prepared. 25 a) {4,5-Bis-(4-chloro-phenyl)-2-[2-(2-dimethylamino-ethoxy)-4-methoxy-phenyl] 4,5-dihydro-imidazol-1-yl}-piperazin-1-yl-methanone. HR-MS (ES, m/z) calculated for C31H36N503Cl2 [(M+H)+] 596.2190, observed 596.2196 WO 03/051359 PCT/EP02/13904 - 68 C N-. N CI k N b) { 4,5-Bis-(4-chloro-phenyl)-2- [2-(2-imidazol- 1 -yl-ethoxy)-4-methoxy-phenyl] 4,5-dihydro-imidazol-1-yl}-piperazin-1-yl-methanone. HR-MS (ES, m/z) calculated for C32H33N603C12 [(M+H)+] 619.1986, observed 619.1988. 5 Example 25 [2-(4-Chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol- 1 yl]-piperazin-1-yl-methanone hydrochloride Cl 1 0 )NXN C/C N CI 10 To a solution of 4-chloro-2-fluoro-benzonitrile (1.0 g, 6.428 mmol) in ethanol (10 mL) were added sodium ethoxide solution (4.8 mL, 12.86 mmol, 21% wt in ethanol). The reaction mixture was heated at gently reflux for 12 h. The solvent was removed and the residue was partitioned between water (10 mL) and diethyl ether (20 mL). The layers were separated and the product was extracted with diethyl ether (20 mL). The organic layers 15 were washed with brine (5 mL) and dried over anhydrous sodium sulfate. The solids were filtered off and the filtrate was concentrated in vacuo. Purification of the residue by flash chromatography (Biotage system, KP-Sil M 32-63 pm, 60 A silica gel) eluting with 5% ethyl acetate in hexanes yielded 4-chloro-2-ethoxy-benzonitrile (0.67 g, 57%). [2-(4-Chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol- 1 20 yl]-piperazin-1-yl-methanone hydrochloride was prepared from 4-chloro-2-ethoxy- WO 03/051359 PCT/EP02/13904 - 69 benzonitrile in a similar manner as described in example 23. HR-MS (ES, m/z) calculated for C28H28N402C3 [(M+H)+] 557.1273, observed 557.1277. Example 26 5 In a similar manner as described in example 23 and example 25, the following compounds were prepared. a)[2-(4-Chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol 1-yl]-(4-methyl-piperazin-1l-yl)-methanone hydrochloride. HR-MS (ES, m/z) calculated for C29H30N402C2 [(M+H)+] 571.1429, observed 571.1438 CI N l> o/ _ _ _ I - 0
NJ
/ 10 CI b) [2-(4-Chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol 1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone hydrochloride. HR-MS (ES, m/z) calculated for C33H36N402C3 [(M+H)+] 625.1899, observed 625.1908. c) [2-(4-Chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol 15 1-yl]-morpholin-4-yl-methanone. HR-MS (ES, m/z) calculated for C28H27N303C13 [(M+H)+] 558.1113, observed 558.1118. d)1-{4-[2-(4-Chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro imidazole- 1-carbonyl]-piperazin-1-yl}-ethanone. HR-MS (ES, m/z) calculated for C30H30N403C3 [(M+H)+] 599.1378, observed 599.1388. 20 e) [2-(4-Chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol 1-yl] -[4- (2-hydroxy-ethyl)-piperazin- 1-yl] -methanone hydrochloride. HR-MS (ES, m/z) calculated for C30H32N403C3 [(M+H)+] 601.1535, observed 601.1543.
WO 03/051359 PCT/EP02/13904 - 70 f)4- [2-(4-Chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro imidazole-1-carbonyl]-piperazin-2-one. HR-MS (ES, m/z) calculated for C28H26N403C13 [(M+H)+] 571.1065, observed 571.1071. 5 Example 27 [4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-isopropoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-piperazin-1-yl-methanone C10 o ci 0 To a solution of 4-bromo-benzene-1,3-diol (1.50 g, 7.94 mmol) in acetone (10 mL) o10 were added potassium carbonate (1.1 g, 7.94 mmol) and 2-iodopropane (1.58 mL, 15.87 mmol). The reaction mixture was heated at gentle reflux for 12 h. The solvent was removed to give a white paste. It was then taken in diethyl ether (50 mL). The white solids were filtered off and the filtrate was concentrated. Purification of the residue by Biotage flash chromatography eluting with 10% ethyl acetate in hexanes gave 4-bromo-3 15 isopropoxy-phenol (0.77 g, 42%). To a solution of 4-bromo-3-isopropoxy-phenol (0.50 g, 2.16 mmol) in acetone (3 mL) were added potassium carbonate (0.30 g, 2.16 mmol) and ethyl iodide (0.35 mL, 4.33 mmol). The reaction mixture was heated at gentle reflux for 12 h. The solvent was removed to give a white paste. It was then taken in diethyl ether (50 mL). The white solids 20 were filtered off and the filtrate was concentrated. Purification of the residue by Biotage flash chromatography eluting with 10% ethyl acetate in hexanes gave 1-bromo-4-ethoxy-2 isopropoxy-benzene (0.48 g, 86%). To a solution of 1-bromo-4-ethoxy-2-isopropoxy-benzene (0.48 g, 1.85 mmol) in DMF (5 mL) was added zinc cyanide (217 mg, 1.85 mmol). The reaction was degassed by 25 passing argon through the mixture for 2 h before tetrakis(triphenylphosphine)-palladium (0) (0.21 g, 0.185 mmol) was added. The reaction mixture was heated at 100-105 oC under WO 03/051359 PCT/EPO2/13904 -71 argon for 12 h. The reaction mixture was taken up in diethyl ether (50 mL) and saturated sodium bicarbonate solution (5 mL). The product was extracted with diethyl ether (2 x 30 mL). The organic layers were washed with water (1 x 10 mL) and brine (1 x 10 mL), dried (sodium sulfate) and concentrated. Purification of the crude by Biotage flash 5 chromatography eluting with 10-15% ethyl acetate in hexanes gave 4-ethoxy-2 isopropoxy-benzonitrile as a clear oil (0.31 g, 81%). Hydrogen chloride gas was passed through a solution of 4-ethoxy-2-isopropoxy benzonitrile (0.30 g, 1.46 mmol) in absolute ethanol (100 mL) in a pressure tube for 45 min at 0 oC. The tube was sealed and stirred at room temperature for 4 d. The pressure 10 was released only after the tube is cooled to 0 oC. Evaporation of the solvents and trituration of the residue in diethyl ether gave ethyl 4-ethoxy-2-isopropoxy-benzimidate hydrochloride which was used without further purification. A mixture of crude ethyl 4-ethoxy-2-isopropoxy-benzimidate hydrochloride and meso-1,2-bis-(4-chloro-phenyl)-ethane-1,2-diamine (0.41 g, 1.46 mmol, prepared 15 according to the procedure described by Vogtle, F.; Goldschmitt, E. Chem. Ber. 1976, 109, 1-40) and triethylamine (0.205 mL, 1.46 mmol) in ethanol (25 mL) was heated at reflux for 3 h. The solvent was removed to give a yellow paste. Aqueous sodium bicarbonate was added and it was extracted with methylene chloride. The combined organic extracts were washed with water and brine, and dried over sodium sulfate. Chromatography of the 20 residue over silica gel with 70% ethyl acetate-hexane gave 4,5-bis-(4-chloro-phenyl)-2-(4 ethoxy-2-isopropoxy-phenyl)-4,5-dihydro-1H-imidazole (0.50 g, 47%). Phosgene (0.325 mL, 0.64 mmol, 1.93 M in toluene) was added dropwise to a mixture of triethylamine (0.126 mL, 0.896 mmol) and 4,5-bis-(4-chloro-phenyl)-2-(4 ethoxy-2-isopropoxy-phenyl)-4,5-dihydro-1H-imidazole (60 mg, 0.128 mmol) in 25 methylene chloride (5 mL) at 0 'C. The reaction mixture was stirred for 30 min at 0 oC and evaporated. The residue was kept under high vacuum for 30 min. Methylene chloride (5 mL) was added to the residue and the solution was added dropwise to a solution of piperazine (0.22 mg, 2.56 mmol) in methylene chloride (5 mL) at 0 oC over 15 min. After 1 h, the reaction was worked up with aqueous sodium bicarbonate. The mixture was 30 extracted with methylene chloride and washed with water and brine. The organic extracts were dried over sodium sulfate and evaporated. Purification using reverse phase HPLC gave [4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-isopropoxy-phenyl)-4,5-dihydro-imidazol- WO 03/051359 PCT/EPO2/13904 - 72 1-yl]-piperazin-1-yl-methanone ( 6.5 mg, 8%). HR-MS (ES, m/z) calculated for C31H35N403Cl2 [(M+H)+] 581.2081, observed 581.2086. Example 28 5 In a similar manner as described in example 27 the following compounds were prepared. a) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-5-methoxy-phenyl)-4,5-dihydro imidazol-1-yl]-piperazin-1-yl-methanone, trifluoroacetic acid salt. HR-MS (ES, m/z) 10 calculated for C29H31N403C12 [(M+H)+] 553.1768, observed 553.1776 I 0 N c- N o 0 rI F O b) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-5-methoxy-phenyl)-4,5-dihydro imidazol-1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone was prepared by sulfonylation of [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-5-methoxy-phenyl)-4,5-dihydro 15 imidazol-1l-yl]-piperazin-1-yl-methanone (example 28a). HR-MS (ES, m/z) calculated for C30H33N405SC12 [(M+H)+] 631.1543, observed 631.1548. c) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-5-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-[4-(2-hydroxy-ethyl)-piperazin- 1 -yl] -methanone hydrochloride. HR-MS (ES, m/z) calculated for C31H35N404CI2 [(M+H)+] 597.2030, observed 597.2037. 20 d) [4,5-Bis-(4-chloro-phenyl)-2-(2,5-diethoxy-phenyl)-4,5-dihydro-imidazol-1-yl] piperazin-1-yl-methanonehydrochloride. HR-MS (ES, m/z) calculated for C30H33N403C12 [(M+H)+] 567.1924, observed 567.1928. e)[4,5-Bis-(4-chloro-phenyl)-2-(2,5-diethoxy-phenyl)-4,5-dihydro-imidazol-1-yl] (4-methanesulfonyl-piperazin-1-yl)-methanone was prepared by sulfonylation of [4,5-bis- WO 03/051359 PCT/EP02/13904 - 73 (4-chloro-phenyl)-2-(2,5-diethoxy-phenyl)-4,5-dihydro-imidazol- 1-yl] -piperazin- 1-yl methanone (example 28d). HR-MS (ES, m/z) calculated for C3 1H35N405SC12 [(M+H)+] 645.1700, observed 645.1714. f)[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-isopropoxy-phenyl)-4,5-dihydro 5 imidazol-1-yl] - [4-(2-hydroxy-ethyl)-piperazin- l-yl]-methanone. HR-MS (ES, m/z) calculated for C33H39N404C2 [(M+H)+] 625.2343, observed 625.2350. g)4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-isopropoxy-phenyl)-4,5-dihydro imidazole- 1 -carbonyl]-piperazin-2-one. HR-MS (ES, m/z) calculated for C31H33N404C12 [(M+H)+] 595.1874, observed 595.1879. 10 h)[4,5-Bis-(4-chloro-phenyl)-2-(5-ethoxy-2-isopropoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-piperazin- 1-yl-methanone. HR-MS (ES, m/z) calculated for C31H35N403C12 [(M+H)+] 581.2081, observed 581.2088. i) [4,5-Bis-(4-chloro-phenyl)-2-(5-ethoxy-2-isopropoxy-phenyl)-4,5-dihydro imidazol- l-yl]- (4-methanesulfonyl-piperazin- 1-yl)-methanone was prepared by 15 sulfonylation of [4,5-bis-(4-chloro-phenyl)-2-(5-ethoxy-2-isopropoxy-phenyl)-4,5 dihydro-imidazol-1-yl]-piperazin-1-yl-methanone (example 28 h). HR-MS (ES, m/z) calculated for C32H37N405SC12 [(M+H)+] 659.1856, observed 659.1864. j) [4,5-Bis-(4-chloro-phenyl)-2-(5-ethoxy-2-isopropoxy-phenyl)-4,5-dihydro imidazol- l-yl] - [4- (2-hydroxy-ethyl)-piperazin- 1-yl] -methanone hydrochloride. HR-MS 20 (ES, m/z) calculated for C33H39N404C2 [(M+H)+] 625.2343, observed 625.2352. k)1-{4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-isopropoxy-phenyl)-4,5-dihydro imidazole-l1-carbonyl]-piperazin-1-yl}-ethanone. HR-MS (ES, m/z) calculated for C33H37N404C12 [(M+H)+] 623.2187, observed 623.2194. 1)1-{4-[4,5-Bis-(4-chloro-phenyl)-2-(5-ethoxy-2-isopropoxy-phenyl)-4,5-dihydro 25 imidazole-1-carbonyl]-piperazin-1-yl}-ethanone. HR-MS (ES, m/z) calculated for C33H37N404C2 [(M+H)+] 623.2187, observed 623.2195. m)[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-isopropoxy-phenyl)-4,5-dihydro imidazol-1-yl] - (4-pyrrolidin-1-yl-piperidin-1-yl)-methanone. HR-MS (ES, m/z) calculated for C36H43N403C2 [(M+H)+] 649.2707, observed 649.2717.
WO 03/051359 PCT/EPO2/13904 - 74 n) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-5-methoxy-phenyl)-4,5-dihydro imidazol-1-yl]-piperazin-1-yl-methanone, trifluoroacetic acid salt. HR-MS (ES, m/z) calculated for C30H33N403CI2 [(M+H)+] 567.1924, observed 567.1929. o)[4,5-Bis-(4-chloro-phenyl)-2-(2,4-diisopropoxy-phenyl)-4,5-dihydro-imidazol-1 5 yl]-piperazin-1-yl-methanone. HR-MS (ES, m/z) calculated for C32H37N403C12 [(M+H)+] 595.2237, observed 595.2244. p)[4,5-Bis-(4-chloro-phenyl)-2-(2,5-diisopropoxy-phenyl)-4,5-dihydro-imidazol-1 yl]-piperazin-1-yl-methanone hydrochloride. HR-MS (ES, m/z) calculated for C32H37N403C2 [(M+H)+] 595.2237, observed 595.2243. 10 Example 29 1- [4,5-Bis-(4-chloro-phenyl)-2-(2-methoxy-5-morpholin-4-yl-methyl-phenyl)-4,5 dihydro-imidazol- l-yl]-2-methyl-propan- 1-one d0 ci / N. 0 N O 15 To a solution of 4- {3-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro- 1H-imidazol-2-yl]-4 methoxy-benzyl}-morpholine (100 mg, 0.20 mmol, as in the U.S. Provisional applications incorporated by reference herein, Example 31) in methylene chloride (10 mL) were sequentially added triethylamine (0.10 mL, 0.712 mmol) and isobutyryl chloride (42 mL, 0.392 mmol). The reaction mixture was stirred for 12 h. The solvents were removed under 20 reduced pressure. Saturated sodium bicarbonate (2 mL) and methylene chloride (20 mL) were added and the layers were separated. The aqueous layer was extracted with methylene chloride (1 x 100 mL). The combined organic extracts were evaporated. Purification of the crude residue by Biotage flash chromatography eluting with 0-5% methanol in ethyl acetate gave 1-[4,5-bis-(4-chloro-phenyl)-2-(2-methoxy-5-morpholin-4-ylmethyl 25 phenyl)-4,5-dihydro-imidazol- 1 -yl]-2-methyl-propan- 1-one. HR-MS (ES, m/z) calculated for C31H34N303CI2 [(M+H)+] 566.1972, observed 566.1977. Example 30 WO 03/051359 PCT/EP02/13904 - 75 In an analogous manner as described in example 29, the following compounds were prepared. a) 1-[4,5-Bis-(4-chloro-phenyl)-2-(3-hydroxymethyl-5-methoxy-phenyl)-4,5 dihydro-imidazol- 1-yl]-2-methyl-propan- 1-one from {3- [4,5-bis-(4-chloro-phenyl)-4,5 5 dihydro-1H-imidazol-2-yl]-5-methoxy-phenyl}-methanol, as in the U.S. Provisional applications incorporated by reference herein, Example 33. HR-MS (ES, m/z) calculated for C27H27N203C2 [(M+H)+] 497.1393, observed 497.1402 CI N - 0 Cl 0 b) 1- [4,5-Bis-(4-chloro-phenyl)-2-(3-hydroxymethyl-5-methoxymethyl-phenyl) 10 4,5-dihydro-imidazol-1l-yl]-ethanone from sodium {3-[4,5-bis-(4-chloro-phenyl)-4,5 dihydro- 1 H-imidazol-2-yl] -5-methoxymethyl-phenyl} -methanol, as in the U.S. Provisional applications incorporated by reference herein, Example 35. HR-MS (EI, m/z) calculated for C26H24N203C12 (M+) 482.1164, observed 482.1161. c) 1-[4,5-Bis-(4-chloro-phenyl)-2-(3-methoxy-5-methoxymethyl-phenyl)-4,5 15 dihydro-imidazol- l-yl] -2-methyl-propan- 1-one from 4,5-bis-(4-chloro-phenyl)-2-(3 methoxy-5-methoxymethyl-phenyl)-4,5-dihydro-1H-imidazole, as in the U.S. Provisional applications incorporated by reference herein, Example 34, HR-MS (m/z) calculated for C28H29N203C2 [(M+H)+] 511.1550, observed 511.1556. d)3-[4,5-Bis-(4-chloro-phenyl)- 1 -isobutyryl-4,5-dihydro- 1H-imidazol-2-yl] -5 20 methoxymethyl-benzoic acid from 3-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H imidazol-2-yl]-5-methoxymethyl-benzoate, as in the U.S. Provisional applications incorporated by reference herein, Example 40, HR-MS (ES, m/z) calculated for C28H27N204C2 [(M+H)+] 525.1343, observed 525.1347. e) 1- [4,5-Bis-(4-chloro-phenyl)-2-(5-ethoxymethyl-2,4-dimethoxy-phenyl)-4,5 25 dihydro-imidazol- l-yl]-2-methyl-propan- 1-one from 4,5-Bis-(4-chloro-phenyl)-2-(5 ethoxymethyl-2,4-dimethoxy-phenyl)-4,5-dihydro-l1H-imidazole as in the U.S. Provisional applications incorporated by reference herein, Example 32, WO 03/051359 PCT/EPO2/13904 - 76 Example 31 [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-6-methoxy-phenyl)-4,5-dihydro-imidazol 1-yl] -piperazin- 1 -yl-methanone Cl 0 N ... N 5 Phosgene (0.147 mL, 0.283 mmol, 1.93 M in toluene) was added to a stirred solution of 4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-6-methoxy-phenyl)-4,5-dihydro- 1H-imidazole (described in previous patent) (25 mg, 0.0566 mmol) and triethylamine (39 mL, 0.283 mmol) in THF (2 mL) at 0 oC over a period of 5 min. The mixture was stirred for 3 h and 10 evaporated. The residue was dissolved in methylene chloride (2 mL) and added dropwise to a stirred solution of piperazine (24 mg, 0.283 mmol) in methylene chloride (2 mL) at room temperature for 3 h. The mixture was diluted with aqueous sodium bicarbonate and extracted with methylene chloride. The organic extracts were washed with brine and dried over sodium sulfate. Evaporation of the solvents and chromatography of the residue over 15 silica gel using 0-10% methanol in methylene chloride gave [4,5-bis-(4-chloro-phenyl)-2 (2-ethoxy-6-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-piperazin-1-yl-methanone (19 mg, 61%). HR-MS (ES, m/z) calculated for C29H31N403C2 [(M+H)+] 553.1768, observed 553.1770.
WO 03/051359 PCT/EP02/13904 - 77 Example 32 [4,5-bis-(4-chloro-phenyl)-2-(5-ethoxymethyl-2,4-dimethoxy-phenyl)-4,5-dihydro imidazol- l-yl] -piperazin-1-yl-methanone CI 0 N / 1 0 5 In a similar manner as described in example 31, the named compound was prepared from 4,5-bis-(4-chloro-phenyl)-2-(5-ethoxymethyl-2,4-dimethoxy-phenyl)-4,5-dihydro 1H-imidazole (described in previous patent). HR-MS (ES, m/z) calculated for C31H35N404C12 [(M+H)+] 597.2030, observed 597.2034. 10 Example 33 [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1l-yl]-[4-(2-hydroxy-propyl)-piperazin-1-yl]-methanone 01/ 10 N I )-0 c o The compound was prepared by the treatment of [4,5-bis-(4-chloro-phenyl)-2-(2 15 isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1l-yl]-piperazin- 1-yl-methanone (example 10g) with propylene oxide in methanol for 7 h at 45 0 C in a sealed tube. HR-MS (ES, m/z) calculated for C33H38N404C2 [(M+H)+] 625.2343, observed 625.2350.
WO 03/051359 PCT/EP02/13904 - 78 Example 34 In a similar manner as described in examples 33, the following compounds were prepared. a) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro 5 imidazol- l-yl]-threo[4-(2-hydroxy- 1-methyl-propyl)-piperazin-1-yl] -methanone. HR-MS (ES, m/z) calculated for C34H40N404C2 [(M+H)+] 639.2500, observed 639.2508. ci CI / 0 N 0I \ N °'=0 b) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl]-erythro[4-(2-hydroxy- 1-methyl-propyl)-piperazin-1-yl]-methanone. HR 10 MS (ES, m/z) calculated for C34H40N404C12 [(M+H)+] 639.2500, observed 639.2507. Example 35 1-{4- [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazole-l1-carbonyl]-piperazin-1-yl}-propan-2-one C 10 N I 0 N N CI: 15 O The compound was prepared by the treatment of [4,5-bis-(4-chloro-phenyl)-2-(2 isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-piperazin-1-yl-methanone WO 03/051359 PCT/EP02/13904 - 79 (example 10g) with chloroacetone and triethylamine at 40'C overnight. HR-MS (ES, m/z) calculated for C33H36N404C12 [(M+H)+] 623.2187, observed 623.2194. Example 36 5 In a similar manner as described in examples 9, the following compounds were prepared. a) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl] -[ 1,4] diazepan- 1-yl-methanone. HR-MS (ES, m/z) calculated for C31H34N403C12 [(M+H)+] 581.2081, observed 581.2086. 01 10 N N o 10 N b) 4-[4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazole-1-carbonyl]-1-methyl-piperazin-2-one. HR-MS (ES, m/z) calculated for C31H32N404C12 [(M+H)+] 595.1874, observed 595.1880. c) 1- {4-[4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 15 dihydro-imidazole- 1 -carbonyl]-piperazin- l-yl}-2-methyl-propan-1-one. HR-MS (ES, m/z) calculated for C34H38N404C2 [(M+H)+] 637.2343, observed 637.2348. d) 4-[4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazole-1-carbonyl]-piperazine-1-carbaldehyde. HR-MS (ES, m/z) calculated for C31H32N404C2 [(M+H)+] 595.1874, observed 595.1882. 20 WO 03/051359 PCT/EP02/13904 -80 Example 37 In a similar manner as described in example 9, the following compounds were prepared: a) 4- {4,5-Bis-(4-chloro-phenyl)-2- [4-methoxy-2-(2,2,2-trifluoro-ethoxy)-phenyl] 5 4,5-dihydro-imidazole- 1-carbonyll}-piperazin-2-one FF CI F ' N CH 3 Cl N The compound was prepared from 4,5-bis-(4-chloro-phenyl)-2-[4-methoxy-2 (2,2,2-trifluoro-ethoxy)-phenyl]-4,5-dihydro-l1H-imidazole, as in the U.S. Provisional applications incorporated by reference herein, example 47a. HR-MS (ES, m/z) calculated 10 for C29H25N404F3C2 [(M+H)+] 621.1278, observed 621.1285. b) 4-{4,5-Bis-(4-bromo-phenyl)-2- [4-methoxy-2-(2,2,2-trifluoro-ethoxy)-phenyl] 4,5-dihydro-imidazole-l1-carbonyl}-piperazin-2-one from 4,5-bis-(4-bromo-phenyl)-2- [4 methoxy-2-(2,2,2-trifluoro-ethoxy)-phenyl]-4,5-dihydro-1H-imidazole, as in the U.S. Provisional applications incorporated by reference herein, example 47b. HR-MS (ES, m/z) 15 calculated for C29H25N404F3Br2 [(M+H)+] 709.0268, observed 709.0280. c) [4,5-Bis-(4-ethynyl-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone from 4,5-bis-(4-ethynyl phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole, as in the U.S. Provisional applications incorporated by reference herein, example 47d. HR-MS (ES, m/z) 20 calculated for C29H25N404F3Br2 [(M+H)+] 615.3330, observed 615.3319. d) 1-{4-[2-(5-Chloro-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro imidazole-l1-carbonyl]-piperazin-1l-yl}l-ethanone from 2-(5-Chloro-2-isopropoxy-phenyl) 4,5-bis-(4-chloro-phenyl)-4,5-dihydro- 1H-imidazole, as in the U.S. Provisional WO 03/051359 PCT/EPO2/13904 -81 applications incorporated by reference herein, example 46. HR-MS (ES, m/z) calculated for C31H31N303C13 [(M+H)+] 613.1535, observed 613.1543. Example 38 5 In a similar manner as described in examples 3, the following compounds were prepared from 4-(4-chloro-phenyl)-5-(4-ethynyl-phenyl)-2-(2-isopropoxy-4-methoxy phenyl)-4,5-dihydro-1H-imidazole, as in the U.S. Provisional applications incorporated by reference herein, example 47e: a) [5-(4-Chloro-phenyl)-4-(4-ethynyl-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl) 10 4,5-dihydro-imidazol-1l-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone. HR-MS (ES, m/z) calculated for C37H41N403C [(M+H)+] 625.2940, observed 625.2943. HC O 3 N 0 O N
-CH
3 00 Cl N b)4-{4,5-Bis-(4-bromo-phenyl)-2-[4-methoxy-2-(2,2,2-trifluoro-ethoxy)-phenyl] 4,5-dihydro-imidazole- 1-carbonyl}-piperazin-2-one [4-(4-Chloro-phenyl)-5-(4-ethynyl 15 phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-pyrrolidin- 1 yl-piperidin-1-yl)-methanone. HR-MS (ES, m/z) calculated for C37H41N403C1 [(M+H)+] 625.2940, observed 625.2943.
WO 03/051359 PCT/EPO2/13904 - 82 Example 39 In Vitro Activity Assay The ability of the compounds to inhibit the interaction between p53 and MDM2 proteins was measured by an ELISA (Enzyme-Linked Immuno Sorbent Assay) in which 5 recombinant GST-tagged MDM2 binds to a peptide that resembles the MDM2-interacting region of p53 (Bottger et al., J. Mol. Bio. 1997, Vol. 269, pgs. 744-756). This peptide is immobilized to the surface of a 96 well plate via N-terminal biotin which binds to streptavidin-coated wells. MDM2 is added to each well in the presence of anti-MDM2 mouse monoclonal antibody (SMP-14, Santa Cruz Biotech). After removal of the 10 unbound MDM2 protein, a peroxydase-linked secondary antibody (anti-mouse IgG, Roche Molecular Biochemicals) and the amount of peptide-bound MDM2 is determined colorimetrically by the addition of a peroxydase substrate (MTB Microwell Peroxydase Substrate System, Kirkegaard & Perry Labs). Test plates were prepared by coating with streptavidin (5 mg/ml in PBS) for 2 hours 15 followed by a PBS (phosphate-buffered saline) wash and overnight blocking with 150 ml of blocking buffer containing 2 mg/ml bovine serum albumin (Sigma) and 0.05% Tween 20 (Sigma) in PBS at 4oC. Biotinylated peptide (1 mM) is added to each well in 50 ml of blocking buffer and washed extensively after 1 h incubation. Test compounds were diluted in a separate 96 well plate and added in triplicate to a compound incubation plate 20 containing a mix of the MDM2 protein and anti-MDM2 antibody. After 20 min incubation, the content of the plate is transferred to the test plate and incubated for an additional 1 hour. The secondary anti-mouse IgG antibody is added to the test plate preceeded and followed by a triple wash with 0.05% Tween 20 in PBS. Finally, peroxydase substrate is added to each well and the absorption was read using a plate reader (MR7000, 25 Dynatech) at 450nm. The inhibitory activity of the test compounds was measured as a percentage of the bound MDM2 in treated vs. untreated wells and IC50 was calculated.
Claims (38)
1. A compound of formula I Y. \/X, N I 5 and the pharmaceutically acceptable salts and esters thereof, wherein R is -C=ORI, wherein R1 is selected from CI-C 6 alkyl, -C=CHCOOH, -NHCH 2 CH 2 R2, N(CH 2 CH 2 OH)CH 2 CH 2 OH, -N(CH 3 )CH 2 CH 2 NCH 3 , N(CH 3 )CH 2 CH 2 N(CH 3 )CH 3 , saturated 4-, 5- and 6-membered rings, and 10 saturated and unsaturated 5- and 6- membered rings containing at least one hetero atom wherein the hetero atom is selected from S, N and O and being optionally substituted with a group selected from C 1 -C 6 alkyl, -C=O-R5, -OH, C 1 -C 6 alkyl optionally substituted with hydroxy, C 1 -C 6 alkyl optionally substituted with -NH 2 , -N-C 1 -C 6 alkyl, -SO 2 CH 3 , =0, -CH 2 C=OCH 3 , and 5 15 and 6-membered saturated rings containing at least one hetero atom selected from S, N and O, wherein R5 is selected from H, C 1 -C 6 alkyl, -NH 2 , -N- CI-C 6 alkyl, C 1 -C 6 alkyl optionally Substituted with hydroxy, and C 1 -C 6 alkyl optionally substituted with NH 2 , R2 is selected from -N(CH 3 )CH 3 , -NCH 2 CH 2 NH 2 , -NH 2 , morpholinyl and 20 piperazinyl, X1, X2 and X3 are independently selected from -OH, C 1 -C 2 alkyl, C 1 -C 6 alkoxy, -Cl,-Br, -F, -CH 2 OCH 3 , and -CH 2 OCH 2 CH 3 , or one of X1, X2 or X3 is H and the other two are independently selected from hydroxy, C I -C 6 alkyl, C 1 -C 6 alkoxy, Cl, Br, F, -CF 3 , -CH 2 OCH 3 , -CH 2 0CH 2 CH 3 , -OCH 2 CH 2 R3, - WO 03/051359 PCT/EPO2/13904 - 84 OCH 2 CF 3 , and -OR4, or one of X1, X2 or X3 is H and the other two taken together with the two carbon atoms and the bonds between them from the benzene ring to which they are optionally substituted form a 5- or 6-membered saturated ring that contains at least one hetero atom selected from S, N, and O, 5 wherein R3 is selected from -F, -OCH 3 , -N(CH 3 )CH 3 , -Cl, -Br, unsaturated 5- and 6 membered rings containing at least one hetero atom wherein the hetero atom is selected from S, N and O, R4 is a 3- to 5- membered saturated ring and 10 Y1 and Y2 are each independently selected from -Cl, -Br, -NO 2 , -C=N, and -C=CH.
2. The compound according to claim 1, wherein Y1 and Y2 are each independently selected from -Cl and -Br. 15
3. The compound according to claim 1, wherein R1 is selected from morpholinyl, piperazinyl, piperadinyl, cyclopentyl, cyclohexyl, thiophenyl, isoxazolyl, and furanyl,piperazinyl substituted with at least one group selected from C 1 -C 3 alkyl, -C 1 -C 2 alkoxy, -C=OCH 3 , -SO 2 CH 3 , -C=O, -OH,-CH 2 NH 2 , -C=OCH 2 NH 2 , -C=OCH 2 OH, -C=OC(OH)CH 2 OH,-CH 2 C(OH)-CH 2 OH, -C=ON(CH 2 -) 2 , 20 -C=ONH 2 , and -C=ON(CH 3 )CH 3 ,-C=OCH(CH 3 ) 2, -CH 2 C=OCH 3 , -CH 2 CH(OH)CH 3 , -CH(CH 3 )CH(OH)CH 3 and -CH 2 CH 2 OH.
4. The compound according to claim 1, wherein one of Xl, X2 and X3 is H and the other two are independently selected from hydroxy, C 1 -C 6 alkoxy, Cl, Br, F, 25 -CH 2 OCH 3 , -CH 2 OCH 2 CH 3 , Cl-C 2 alkyl, -OCH 2 CH 2 R 3 and -OR4,wherein R3 is selected from -F, -OCH 3 , -N(CH 3 )CH 3 , unsaturated 5-membered rings containing at least one hetero atom wherein the hetero atom is selected from S, N and O, and wherein R4 is cyclopentyl, or one of X1, X2 or X3 is H and the other two taken together with the two carbon atoms and the bonds between them from the benzene WO 03/051359 PCT/EPO2/13904 - 85 ring to which they are substituted form a 5- membered saturated ring that contains at least one hetero atom selected from S, N and O.
5. The compound according to claim 4, wherein one of Xl, X2 or X3 is H, the other 5 two are independently selected from -OCH 3 and -CH 2 OCH 2 CH 3 .
6. The compound according to claim 4, wherein one of X1, X2 or X3 is H, and one or both of the other two is -O-C 1 alkyl, -O-C 2 alkyl or -O-C 3 alkyl. o10
7. The compound according to claim 4, wherein R3 is imidazolyl.
8. The compound according to claim 1, wherein X3 is H and Xl and X2 together with the two carbon atoms and the bonds between them from the benzene ring to they are substituted form a 6-membered saturated ring that contains one hetero atom which 15 is O.
9. The compound according to claim 1, wherein one of the groups X1, X2 or X3 is H at meta position, the group at ortho position is selected from C 1 -C 6 alkoxy and -OCH 2 CF 3 , and the group at para position is C 1 -C 6 alkoxy. 20
10. The compound according to claim 9, wherein the X1, X2 or X3 group at ortho position is selected from ethoxy, isopropoxy and -OCH 2 CF 3 , and the group at para position is selected from methoxy and ethoxy. 25
11. The compound according to claim 10, wherein R1 is selected from piperazinyl and substituted piperazinyl. WO 03/051359 PCT/EPO2/13904 - 86
12. The compound according to claim 1, wherein one of the groups X1, X2 or X3 is H at meta position, the group at the ortho position is C 1 -C 6 alkoxy and the group at the para position is -Cl, -Br or -F, or one of the groups X1, X2 or X3 is H at para 5 position, and the two other groups at ortho position are C 1 -C 6 alkoxy and the group at meta position is -Cl, -Br or -F.
13. A compound of formula II Y 1 x 4 N N N R I 10 and the pharmaceutically acceptable salts and esters thereof, wherein R is -C=OR1, R1 is selected from C 1 -C 6 alkyl, saturated 5- and 6-membered rings, saturated 5- and 6-membered rings containing at least one hetero atom wherein the hetero atom is selected from S, N and O and being optionally substituted with a group 15 selected from C 1 -C 2 alkyl, C 1 -C 3 alcohol, -N(CH 3 )CH 3 , -C=OCH 3 , and 5 and 6-membered rings containing at least one hetero atom wherein the hetero atom is selected from S, N, and O, X4 is selected from C 1 -C 2 alkyl, CI-C 6 alkoxy, fluoroethoxy, -Cl, -Br, -F, OCH 2 C=OOQ, -0- C 1 -C 6 alkyl, -OCH2-cyclopropyl, -CH 2 0CH 2 -phenyl, 20 saturated and unsaturated 5- and 6-membered rings, saturated and unsaturated 5- and 6-membered rings containing at least one hetero atom wherein the hetero atom is selected from S, N and O, wherein Q is selected from H, and C 1 -C 6 alkyl, Y1 and Y2 are independently selected from -Cl, -Br, -NO 2 , -C= N and -C=H, WO 03/051359 PCT/EP02/13904 - 87 with the proviso that where YI and Y2 are both -Cl, and R1 is -CH 3 or phenyl, then X4 is not -Cl.
14. The compound according to claim 13, wherein X4 is selected from -CH 3 , C 1 -C 5 5 alkoxy, -Cl, -Br, -OCH 2 C=OOQ, phenyl and pyrrolidinyl, wherein Q is H or -CH2CH3.
15. The compound according to claim 14, wherein X4 is selected from -CH 3 , C 1 -C 6 alkoxy, -OCH 2 C=OOQ, phenyl and pyrrolidinyl, wherein Q is H or-CH 2 CH 3 . 10
16. The compound according to claim 13, wherein R1 is selected from -CH(CH 3 )CH 3 , piperazinyl, piperazinyl substituted with a group selected from -CH 3 , -CH 2 CH 2 OH, and -C=OCH 3 , piperadinyl, and piperadinyl substituted with a group selected from pyrrolidinyl, piperadinyl, and -N(CH 3 )CH 3 . 15
17. The compound according to claim 13, wherein C 1 -C 6 alkyl is selected from C 1 alkyl, C 2 alkyl and C 3 alkyl.
18. The compound according to claim 13, wherein Y1 and Y2 are independently selected 20 from -Cl and -Br.
19. The compound according to claim 18, wherein X4 is C 1 -C 6 alkoxy at ortho position. WO 03/051359 PCT/EP02/13904 - 88
20. The compound according to claim 19, wherein the C1-C 6 alkoxy is selected from ethoxy, isopropoxy and 2-fluoroethoxy.
21. The compound according to claim 20, wherein R1 is selected from piperazinyl and 5 substituted piperazinyl.
22. The compound according to claim 1, selected from the group of: a) 1- [4,5-Bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-2-methyl-propan- 1-one; 10 b) 1- [4,5-Bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro imidazol-1-yl] ethanone; c) 1- [4,5-Bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro imidazol- l-yl]-2,2-dimethyl-propan- 1-one; d) [4,5-Bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro-imidazol 15 1-yl]-cyclopentyl-methanone; e) [4,5-Bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro-imidazol 1-yl]-cyclohexyl-methanone; f) [4,5-Bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro-imidazol 1-yl]-thiophen-2-yl-methanone; 20 g) [4,5-Bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro-imidazol 1-yl]-isoxazol-5-yl-methanone; h) [4,5-Bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro-imidazol 1-yl]-furan-2-yl-methanone; i) 1-[4,5-Bis-(4-chloro-phenyl)-2-(2,3-dimethoxy-phenyl)-4,5-dihydro 25 imidazol- l-yl]-2-methyl-propan- 1-one; WO 03/051359 PCT/EPO2/13904 - 89 j) [4,5-Bis- (4-chloro-phenyl)-2- (2,4-dimethoxy-phenyl)-4,5-dihydro-imidazol 1-yl]-(4-methyl-piperazin- 1-yl)-methanone; k) [4,5-Bis-(4-chloro-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro-imidazol 1-yl]-piperazin- 1-yl-methanone; 5 1) [4,5-Bis- (4-chloro-phenyl)-2- (2-fluoro-6-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl] -[4-(2-hydroxy-ethyl)-piperazin- 1-yl] -methanone; m) 1- {4- [4,5-Bis-(4-bromo-phenyl)-2- (2,4-dimethoxy-phenyl)-4,5-dihydro imidazole- 1-carbonyl]-piperazin- 1-yl}-ethanone; n) [4,5-Bis- (4-bromo-phenyl)-2-(2,4-dimethoxy-phenyl)-4,5-dihydro-imidazol 10 1-yl]-[4-(2-hydroxy-ethyl)-piperazin- l-yl]-methanone; o) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone hydrochloride; p) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro 15 imidazol- 1-yl]-(4-methanesulfonyl-piperazin- l-yl)-methanone; q) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-[4-(2-hydroxy-ethyl)-piperazin- l-yl]-methanone; r) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-morpholin-4-yl-methanone; 20 s) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl]- (4-methyl-piperazin- 1-yl)-methanone; t) 1- {4- [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazole- 1-carbonyl] -piperazin- 1-yl}-ethanone; u) 4- [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro 25 imidazole- 1-carbonyl] -piperazin-2-one; v) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- l-yl]-piperazin- 1-yl-methanone; WO 03/051359 PCT/EP02/13904 - 90 w) 1- {4- [4,5-Bis- (4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 dihydro-imidazole- 1-carbonyl]-piperazin- 1-yl} -ethanone; x) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-(4-methanesulfonyl-piperazin- l-yl)-methanone; 5 y) [4,5-Bis- (4-chloro-phenyl)-2- (2-isopropoxy-4-methoxy-phenyl)-4,5- dihydro imidazol- l-yl] - (2,5-dimethyl-piperazin-1-yl)-methanone; z) 4,5-Bis- (4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazole- 1-carboxylic acid bis- (2-hydroxy-ethyl)-amide; aa) [4,5-Bis- (4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro 10 imidazol-1-yl] - (4-ethyl-piperazin- 1 -yl)-methanone; bb) [1,4']Bipiperidinyl- 1'-yl-[4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4 methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-methanone; cc) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1l-yl]-(4-pyrrolidin-1-yl-piperidin-1l-yl)-methanone; 15 dd) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1 -yl] - (4-dimethylamino-piperidin-1-yl)-methanone; ee) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl] -morpholin-4-yl-methanone; ff) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro 20 imidazol-l-yl]-(4-isopropyl-piperazin- 1-yl)-methanone; gg) 4- [4,5-Bis- (4-chloro-phenyl)-2- (2-isopropoxy-4-methoxy-phenyl)-4,5 dihydro-imidazole- 1-carbonyl]-piperazin-2-one; hh) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1l-yl]-(4-hydroxymethyl-piperidin-1-yl)-methanone; 25 ii) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl]- [4-(2-hydroxy-ethyl)-piperidin-1-yl]-methanone; WO 03/051359 PCT/EPO2/13904 -91 jj) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl] -(3-methyl-piperazin- 1-yl)-methanone; kk) 1- {14- [4,5-Bis- (4-chloro-phenyl)-2- (2-isopropoxy-4-methoxy-phenyl)-4,5 dihydro-imidazole- 1-carbonyl]-2-methyl-piperazin- 1-yl}-ethanone; 5 11) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- l-yl]- (4-methanesulfonyl-3-methyl-piperazin- 1 -yl)-methanone; mm) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1l-yl]-(4-hydroxy-piperidin-1-yl)-methanone; nn) (4-Aminomethyl-piperidin- l-yl)- [4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy 10 4-methoxy-phenyl)-4,5-dihydro-imidazol- 1-yl]-methanone; oo) [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl]- [4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone; pp) [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl]-piperazin-1-yl-methanone; 15 qq) [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1l-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone; rr) 1-1{4-[4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazole-l1-carbonyl]-piperazin-1-yl}-ethanone; ss) [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro 20 imidazol-1-yl]-(4-methyl-piperazin-1l-yl)-methanone; tt) 4- [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazole-l1-carbonyl]-piperazine-l1-carbaldehyde; uu) [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; 25 vv) [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1l-yl]-(4-dimethylamino-piperidin-1l-yl)-methanone; WO 03/051359 PCT/EPO2/13904 - 92 ww) [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-(4-isopropyl-piperazin- 1 -yl)-methanone; xx) 4- [4,5-Bis-(4-bromo-phenyl)-2- (2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazole- 1-carbonyl] -piperazin-2-one; and 5 yy) [4,5-Bis-(4-bromo-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-piperazin- 1-yl-methanone.
23. The compound according to claim 1, selected from the group of: a) 1-1{4- [4,5-Bis-(4-bromo-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 10 dihydro-imidazole- 1-carbonyl] -piperazin- 1-yl}-ethanone; b) [4,5-Bis-(4-bromo-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone; c) [4,5-Bis-(4-bromo-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-(4-methyl-piperazin- 1-yl)-methanone; 15 d) [4,5-Bis-(4-bromo-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl] -morpholin-4-yl-methanone; e) [1,4'] Bipiperidinyl- l'-yl- [4,5-bis- (4-bromo-phenyl)-2-(2-isopropoxy-4 methoxy-phenyl)-4,5-dihydro-imidazol- 1-yl]-methanone; f) [4,5-Bis-(4-bromo-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro 20 imidazol-l-yl] -(4-ethyl-piperazin-1-yl)-methanone; g) 4- [4,5-Bis-(4-bromo-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 dihydro-imidazole- 1-carbonyl]-piperazin-2-one; h) [4,5-Bis- (4-cyano-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl] -piperazin- 1-yl-methanone; 25 i) 1-(4-{4,5-Bis-(4-chloro-phenyl)-2- [4-methoxy-2-(2-methoxy-ethoxy) phenyl] -4,5-dihydro-imidazole- 1 -carbonyl}-piperazin- 1-yl)-ethanone; WO 03/051359 PCT/EP02/13904 - 93 j) 1-(4- {4,5-Bis-(4-chloro-phenyl)-2- [2-(2-fluoro-ethoxy)-4-methoxy-phenyl] 4,5-dihydro-imidazole- 1-carbonyl}-piperazin- 1-yl)-ethanone; k) 4- {4,5-Bis-(4-chloro-phenyl)-2- [2-(2-fluoro-ethoxy)-4-methoxy-phenyl]-4,5 dihydro-imidazole- 1 -carbonyl} -piperazin-2-one; 5 1) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl] -piperazin-1-yl-methanone hydrochloride; m) 4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazole-1-carboxylic acid methyl-(2-methylamino-ethyl)-amide, trifluoroacetic acid salt; 10 n) 4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazole-1-carboxylic acid (2-dimethylamino-ethyl)-methyl-amide, trifluoroacetic acid salt; o) 4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazole-1-carboxylic acid (2-dimethylamino-ethyl)-amide, trifluoroacetic 15 acid salt; p) 4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazole-1-carboxylic acid (2-amino-ethyl)-amide, trifluoroacetic acid salt; q) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl] -(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone hydrochloride; 20 r) [4,5-Bis-(4-chloro-phenyl)-2-(4-methoxy-2-propoxy-phenyl)-4,5-dihydro imidazol-1-yl]-piperazin-1-yl-methanone, trifluoroacetic acid salt; s) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone hydrochloride; t) 4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro 25 imidazole-1-carboxylic acid (2-morpholin-4-yl-ethyl)-amide hydrochloride; u) 4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazole-1-carboxylic acid (2-piperazin- 1-yl-ethyl)-amide hydrochloride; WO 03/051359 PCT/EP02/13904 - 94 v) [4,5-Bis-(4-chloro-phenyl)-2-(2-isobutoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl] -piperazin- 1-yl-methanone hydrochloride; w) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl] - (3-methyl-piperazin- 1-yl)-methanone hydrochloride; 5 x) {4,5-Bis-(4-chloro-phenyl)-2-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl]-4,5 dihydro-imidazol-1-yl}-piperazin-1-yl-methanone, trifluoroacetic acid salt; y) {4,5-Bis-(4-chloro-phenyl)-2- [2-(2-fluoro-ethoxy)-4-methoxy-phenyl]-4,5 dihydro-imidazol-1-yl}-piperazin-1-yl-methanone; z) {4,5-Bis-(4-chloro-phenyl)-2-[2-(2-fluoro-ethoxy)-4-methoxy-phenyl]-4,5 10 dihydro-imidazol-1-yl}-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone hydrochloride; aa) 2-Amino- 1- {4- [4,5-bis- (4-chloro-phenyl)-2- (2-isopropoxy-4-methoxy phenyl)-4,5-dihydro-imidazole- 1-carbonyl]-piperazin- 1-yl}-ethanone; bb) 1- {4-[4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 15 dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-2-hydroxy-ethanone; cc) 1- {4-[4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 dihydro-imidazole- 1-carbonyl]-piperazin- 1-yl}-2,3-dihydroxy-propan- 1-one; dd) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1-yl]-[4-(2,3-dihydroxy-propyl)-piperazin-1l-yl]-methanone; 20 ee) 4- [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 dihydro-imidazole- 1-carbonyl] -piperazine- 1-carboxylic acid dimethylamide; ff) 4- [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 dihydro-imidazole-l1-carbonyl]-piperazine-l1-carboxylic acid amide; gg) [4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-phenyl)-4,5-dihydro-imidazol- 1 25 yl]-piperazin-1-yl-methanone; hh) [4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-phenyl)-4,5-dihydro-imidazol- 1 yl] morpholin-4-yl-methanone; WO 03/051359 PCT/EPO2/13904 - 95 ii) [4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-phenyl)-4,5-dihydro-imidazol- 1 yl]- [4-(2-hydroxy-ethyl)-piperazin- 1-yl]-methanone; jj) [4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-phenyl)-4,5-dihydro-imidazol- 1 yl] - (4-methyl-piperazin- 1-yl)-methanone; 5 kk) 1- {4- [4,5-Bis- (4-chloro-phenyl)-2- (2,4-diethoxy-phenyl)-4,5-dihydro imidazole- 1-carbonyl]-piperazin- l-yl}-ethanone; 11) [4,5-Bis- (4-chloro-phenyl)-2- (2,4-diethoxy-phenyl)-4,5-dihydro-imidazol- 1 yl] - (4-methanesulfonyl-piperazin- 1-yl)-methanone; mm) [4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-phenyl)-4,5-dihydro-imidazol- 1 10 yl]-(4-pyrrolidin-1-yl-piperidin-1l-yl)-methanone; nn) [4,5-Bis-(4-bromo-phenyl)-2-(2,4-diethoxy-phenyl)-4,5-dihydro-imidazol- 1 yl]-(4-methyl-piperazin-1l-yl)-methanone; oo) [4,5-Bis-(4-bromo-phenyl)-2-(2,4-diethoxy-phenyl)-4,5-dihydro-imidazol- 1 yl]-(4-ethyl-piperazin-1-yl)-methanone; 15 pp) [4,5-Bis-(4-bromo-phenyl)-2-(2,4-diethoxy-phenyl)-4,5-dihydro-imidazol- 1 yl] -morpholin-4-yl-methanone; qq) 4- [4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-phenyl)-4,5-dihydro-imidazole 1-carbonyl]-piperazine- 1-carboxylic acid amide; rr) 4- [4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-phenyl)-4,5-dihydro-imidazole 20 1-carbonyl]-piperazine- 1-carboxylic acid dimethylamide; ss) [4,5-Bis-(4-chloro-phenyl)-2- (4-dimethylamino-2-ethoxy-phenyl)-4,5 dihydro-imidazol- 1-yl] -piperazin- 1 -yl-methanone; tt) [4,5-Bis- (4-chloro-phenyl)-2- (2-ethoxy-4-ethyl-phenyl)-4,5-dihydro imidazol- 1-yl]-piperazin- 1 -yl-methanone; 25 uu) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-methyl-phenyl)-4,5-dihydro imidazol- 1-yl]-piperazin- 1 -yl-methanone; WO 03/051359 PCT/EP02/13904 - 96 vv) [4,5-Bis-(4-chloro-phenyl)-2-(4-ethyl-2-isopropoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-piperazin-1-yl-methanone; ww) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methyl-phenyl)-4,5-dihydro imidazol- 1-yl]-piperazin-1-yl-methanone; 5 xx) 1-{4- [4,5-Bis-(4-chloro-phenyl)-2-(4-dimethylamino-2-ethoxy-phenyl)-4,5 dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-ethanone; and yy) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-5-methyl-phenyl)-4,5-dihydro imidazol-1-yl]-piperazin-1-yl-methanone, trifluoroacetic acid salt. 10
24. The compound according to claim 1, selected from the group of: a) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-fluoro-phenyl)-4,5-dihydro imidazol- 1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; b) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-fluoro-phenyl)-4,5-dihydro imidazol- 1-yl]-(4-dimethylamino-piperidin-1l-yl)-methanone; 15 c) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-fluoro-phenyl)-4,5-dihydro imidazol- 1-yl]-piperazin-1-yl-methanone; d) [4,5-Bis-(4-chloro-phenyl)-2-(4-fluoro-2-isopropoxy-phenyl)-4,5-dihydro imidazol-1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone; e) [4,5-Bis-(4-chloro-phenyl)-2-(4-fluoro-2-isopropoxy-phenyl)-4,5-dihydro 20 imidazol-1-yl]-(4-dimethylamino-piperidin-1-yl)-methanone; f) [4,5-Bis-(4-chloro-phenyl)-2-(4-fluoro-2-isopropoxy-phenyl)-4,5-dihydro imidazol-1-yl]-(4-methyl-piperazin-1l-yl)-methanone; g) [4,5-Bis-(4-chloro-phenyl)-2-(4-fluoro-2-isopropoxy-phenyl)-4,5-dihydro imidazol-1-yl]-piperazin-1-yl-methanone; 25 h) [4,5-Bis-(4-chloro-phenyl)-2-(4-fluoro-2-isopropoxy-phenyl)-4,5-dihydro imidazol-1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone; WO 03/051359 PCT/EP02/13904 - 97 i) 4- [4,5-Bis-(4-chloro-phenyl)-2-(4-fluoro-2-isopropoxy-phenyl)-4,5-dihydro imidazole- 1-carbonyl]-piperazin-2-one; j) [4,5-Bis-(4-chloro-phenyl)-2-chroman-8-yl-4,5-dihydro-imidazol- 1-yl] piperazin- 1 -yl-methanone; 5 k) 4- [4,5-Bis- (4-bromo-phenyl)-2- (2-ethoxy-4-fluoro-phenyl)-4,5-dihydro imidazole- 1-carbonyl] -piperazin-2-one; 1) [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-fluoro-phenyl)-4,5-dihydro imidazol- 1 -yl]-morpholin-4-yl-methanone; m) [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-fluoro-phenyl)-4,5-dihydro 10 imidazol- 1-yl]-(4-pyrrolidin- 1-yl-piperidin- l-yl)-methanone; n) [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-fluoro-pheny1)-4,5-dihydro imidazol- 1-yl]-(4-dimethylamino-piperidin- 1-yl)-methanone; o) [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-4-fluoro-phenyl)-4,5-dihydro imidazol- 1-yl] -piperazin- 1 -yl-methanone; 15 p) [4,5-Bis-(4-chloro-phenyl)-2-(2-cyclopentyloxy-4-methoxy-phenyl)-4,5 dihydro-imidazol- 1-yl]-piperazin- 1-yl-methanone; q) {4,5-Bis-(4-chloro-phenyl)-2- [2- (2-dimethylamino-ethoxy)-4-methoxy phenyl]-4,5-dihydro-imidazol- 1-yl}-piperazin- 1 -yl-methanone; r) {4,5-Bis- (4-chloro-phenyl)-2- [2- (2-imidazol- 1-yl-ethoxy)-4-methoxy 20 phenyl]-4,5-dihydro-imidazol- 1-yl}-piperazin- 1-yl-methanone; s) [2-(4-Chloro-2-ethoxy-phenyl)-4,5-bis- (4-chloro-phenyl)-4,5-dihydro imidazol- 1-yl]-piperazin- 1-yl-methanone hydrochloride; t) [2-(4-Chloro-2-ethoxy-phenyl)-4,5-bis- (4-chloro-phenyl)-4,5-dihydro imidazol- 1-yl]- (4-methyl-piperazin- 1 -yl)-methanone hydrochloride; 25 u) [2-(4-Chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro imidazol-1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone hydrochloride; WO 03/051359 PCT/EP02/13904 - 98 v) [2- (4-Chloro-2-ethoxy-phenyl)-4,5-bis- (4-chloro-phenyl)-4,5-dihydro imidazol- 1-yl]-morpholin-4-yl-methanone; w) 1- {4- [2- (4-Chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro imidazole- 1-carbonyl] -piperazin- 1-yll}-ethanone; 5 x) [2-(4-Chloro-2-ethoxy-phenyl)-4,5-bis- (4-chloro-phenyl)-4,5-dihydro imidazol- 1-yl]-[4- (2-hydroxy-ethyl)-piperazin- 1-yl] -methanone hydrochloride; y) 4- [2-(4-Chloro-2-ethoxy-phenyl)-4,5-bis- (4-chloro-phenyl)-4,5-dihydro imidazole- 1-carbonyl]-piperazin-2-one; 10 z) [4,5-Bis- (4-chloro-phenyl)-2-(4-ethoxy-2-isopropoxy-phenyl)-4,5-dihydro imidazol- 1-yl] -piperazin- 1-yl-methanone; aa) [4,5-Bis- (4-chloro-phenyl)-2-(2-ethoxy-5-methoxy-phenyl)-4,5-dihydro imidazol-1-yl]-piperazin-1-yl-methanone, trifluoroacetic acid salt; bb) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-5-methoxy-phenyl)-4,5-dihydro 15 imidazol- 1 -yl] -(4-methanesulfonyl-piperazin- 1 -yl)-methanone; cc) [4,5-Bis-(4-chloro-phenyl)-2- (2-ethoxy-5-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-[4-(2-hydroxy-ethyl)-piperazin- l-yl]-methanone hydrochloride; dd) [4,5-Bis-(4-chloro-phenyl)-2-(2,5-diethoxy-phenyl)-4,5-dihydro-imidazol- 1 20 yl]-piperazin- 1-yl-methanone hydrochloride; ee) [4,5-Bis-(4-chloro-phenyl)-2- (2,5-diethoxy-phenyl)-4,5-dihydro-imidazol- 1 yl] -(4-methanesulfonyl-piperazin- 1-yl)-methanone; f) [4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-isopropoxy-phenyl)-4,5-dihydro imidazol- 1-yl] -[4- (2-hydroxy-ethyl)-piperazin- 1-yl] -methanone; 25 gg) 4- [4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-isopropoxy-phenyl)-4,5-dihydro imidazole- 1-carbonyl] -piperazin-2-one; hh) [4,5-Bis-(4-chloro-phenyl)-2-(5-ethoxy-2-isopropoxy-phenyl)-4,5-dihydro imidazol- 1-yl] -piperazin- 1 -yl-methanone; WO 03/051359 PCT/EPO2/13904 - 99 ii) [4,5-Bis-(4-chloro-phenyl)-2-(5-ethoxy-2-isopropoxy-phenyl)-4,5-dihydro imidazol- 1-yl]- (4-methanesulfonyl-piperazin- 1-yl)-methanone; jj) [4,5-Bis- (4-chloro-phenyl)-2-(5-ethoxy-2-isopropoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-[4-(2-hydroxy-ethyl)-piperazin- 1-yl] -methanone 5 hydrochloride; kk) 1- {4- [4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-isopropoxy-phenyl)-4,5 dihydro-imidazole- 1-carbonyl]-piperazin- l-yl}-ethanone; 11) 1-{4- [4,5-Bis-(4-chloro-phenyl)-2-(5-ethoxy-2-isopropoxy-phenyl)-4,5 dihydro-imidazole- 1 -carbonyl]-piperazin- 1-yl} -ethanone; 10 mm) [4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-isopropoxy-phenyl)-4,5-dihydro imidazol-1-yl] - (4-pyrrolidin-1-yl-piperidin- 1 -yl)-methanone; nn) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-5-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-piperazin- 1-yl-methanone, trifluoroacetic acid salt; oo) [4,5-Bis-(4-chloro-phenyl)-2-(2,4-diisopropoxy-phenyl)-4,5-dihydro 15 imidazol- l-yl]-piperazin- 1-yl-methanone; pp) [4,5-Bis-(4-chloro-phenyl)-2-(2,5-diisopropoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-piperazin- 1 -yl-methanone hydrochloride; qq) 1- [4,5-Bis-(4-chloro-phenyl)-2-(2-methoxy-5-morpholin-4-yl-methyl phenyl)-4,5-dihydro-imidazol- l-yl]-2-methyl-propan- 1-one; 20 rr) 1- [4,5-Bis-(4-chloro-phenyl)-2-(3-hydroxymethyl-5-methoxy-phenyl)-4,5 dihydro-imidazol- l-yl]-2-methyl-propan- 1-one; ss) 1- [4,5-Bis-(4-chloro-phenyl)-2-(3-hydroxymethyl-5-methoxymethyl-phenyl) 4,5-dihydro-imidazol-l-yl]-ethanone; tt) 1-[4,5-Bis-(4-chloro-phenyl)-2-(3-methoxy-5-methoxymethyl-phenyl)-4,5 25 dihydro-imidazol- 1-yl] -2-methyl-propan- 1-one; uu) 3- [4,5-Bis- (4-chloro-phenyl)- 1-isobutyryl-4,5-dihydro- 1H-imidazol-2-yl]-5 methoxymethyl-benzoic acid; WO 03/051359 PCT/EPO2/13904 - 100 vv) 1-[4,5-Bis-(4-chloro-phenyl)-2-(5-ethoxymethyl-2,4-dimethoxy-phenyl)-4,5 dihydro-imidazol- 1-yl]-2-methyl-propan- 1-one; ww) [4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-6-methoxy-phenyl)-4,5-dihydro imidazol- 1-yl]-piperazin-1-yl-methanone; and 5 xx) [4,5-bis-(4-chloro-phenyl)-2-(5-ethoxymethyl-2,4-dimethoxy-phenyl)-4,5 dihydro-imidazol-1-yl]-piperazin-1-yl-methanone.
25. The compound according to claim 1, selected from the group of: a) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro 10 imidazol-1-yl]-[4-(2-hydroxy-propyl)-piperazin- 1-yl]-methanone; b) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro imidazol-1l-yl]-threo[4-(2-hydroxy-l1-methyl-propyl)-piperazin-1l-yl] methanone; c) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro 15 imidazol-1-yl]-erythro[4-(2-hydroxy- 1-methyl-propyl)-piperazin-1-yl] methanone; d) 1- {4-[4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 dihydro-imidazole- 1 -carbonyl] -piperazin- 1-yl}-propan-2-one; e) [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro 20 imidazol-1-yl]-[1,4]diazepan-1-yl-methanone; f) 4- [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 dihydro-imidazole-l1-carbonyl]-1l-methyl-piperazin-2-one; g) 1- {4-[4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 dihydro-imidazole-l1-carbonyll -piperazin- 1-yl}-2-methyl-propan- 1 -one; 25 h) 4- [4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 dihydro-imidazole-l1-carbonyl]-piperazine- 1-carbaldehyde; WO 03/051359 PCT/EPO2/13904 - 101 i) 4- {4,5-Bis-(4-chloro-phenyl)-2-[4-methoxy-2-(2,2,2-trifluoro-ethoxy) phenyl]-4,5-dihydro-imidazole- 1 -carbonyl} -piperazin-2-one; j) 4-{4,5-Bis-(4-bromo-phenyl)-2- [4-methoxy-2-(2,2,2-trifluoro-ethoxy) phenyl] -4,5-dihydro-imidazole- 1-carbonyl}l -piperazin-2-one; 5 k) [4,5-Bis-(4-ethynyl-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5 dihydro-imidazol- 1-yl]-(4-pyrrolidin- 1-yl-piperidin-1-yl)-methanone; 1) 1-{4- [2-(5-Chloro-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5 dihydro-imidazole- 1-carbonyl]-piperazin-1l-yl}-ethanone; and m) [5-(4-Chloro-phenyl)-4-(4-ethynyl-phenyl)-2-(2-isopropoxy-4-methoxy 10 phenyl)-4,5-dihydro-imidazol-1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl) methanone.
26. The compound according to claim 13, selected from the group of: a) 1- [4,5-Bis-(4-chloro-phenyl)-2-(2-methoxy-phenyl)-4,5-dihydro-imidazol- 1 15 yl]-2-methyl-propan-1-one; b) 1- [4,5-Bis-(4-chloro-phenyl)-2-p-tolyl-4,5-dihydro-imidazol-1-yl]-ethanone; c) {4- [4,5-Bis-(4-chloro-phenyl)- 1-isobutyryl-4,5-dihydro- 1H-imidazol-2-yl] phenoxy}-acetic acid ethyl ester; d) {4-[4,5-Bis-(4-chloro-phenyl)- 1-isobutyryl-4,5-dihydro- 1H-imidazol-2-yl] 20 phenoxy}-acetic acid; e) 2-Methyl-1-[2,4,5-tris-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-propan 1-one; f) 1-[4,5-Bis-(4-chloro-phenyl)-2-(4-methoxy-phenyl)-4,5-dihydro-imidazol- 1 yl]-ethanone; 25 g) [2- (2-Chloro-phenyl)-4,5-bis- (4-chloro-phenyl)-4,5-dihydro-imidazol- 1-yl] piperazin- 1 -yl-methanone; WO 03/051359 PCT/EPO2/13904 - 102 h) [2-(3-Bromo-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl] piperazin- 1-yl-methanone; i) [2-Biphenyl-3-yl-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-(4 methyl-piperazin- 1 -yl)-methanone; 5 j) [4,5-Bis-(4-chloro-phenyl)-2-(3-pyrrolidin- 1-yl-phenyl)-4,5-dihydro imidazol- 1-yl]-piperazin- 1-yl-methanone; k) [4,5-Bis-(4-bromo-phenyl)-2-(2-methoxy-phenyl)-4,5-dihydro-imidazol- 1 yl]-[4-(2-hydroxy-ethyl)-piperazin- 1-yl]-methanone; 1) 1- [5-(4-Chloro-phenyl)-2-(4-methoxy-phenyl)-4-(4-nitro-phenyl)-4,5 10 dihydro-imidazol- l-yl]-2-methyl-propan- 1-one; m) 1- [4- (4-chloro-phenyl)-2-(4-methoxy-phenyl)-5- (4-nitro-phenyl)-4,5 dihydro-imidazol- l-yl]-2-methyl-propan- 1-one; n) 1- [4,5-Bis-(4-chloro-phenyl)-2- (2-isopropoxy-phenyl)-4,5-dihydro-imidazol 1-yl]-2-methyl-propan- 1-one; 15 o) [4,5-Bis- (4-chloro-phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro-imidazol- 1 yl] -(4-pyrrolidin- 1 -yl-piperidin- 1 -yl)-methanone; p) [4,5-Bis- (4-chloro-phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro-imidazol- 1 yl] -piperazin- 1-yl-methanone; q) [4,5-Bis- (4-chloro-phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro-imidazol- 1 20 yl] -(4-dimethylamino-piperidin- 1 -yl)-methanone; r) [1,4'] Bipiperidinyl- l'-yl- [4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-phenyl) 4,5-dihydro-imidazol- 1-yl]-methanone; s) [4,5-Bis- (4-chloro-phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro-imidazol- 1 yl]- [4-(2-hydroxy-ethyl)-piperazin- 1-yl]-methanone; 25 t) {4,5-Bis- (4-chloro-phenyl)-2- [2-(2-methyl-butoxy)-phenyl]-4,5-dihydro imidazol-1-yl}-piperazin- 1-yl-methanone; WO 03/051359 PCT/EP02/13904 - 103 u) [4,5-Bis-(4-chloro-phenyl)-2- (2-pentyloxy-phenyl)-4,5- dihydro-imidazol- 1 yl] -piperazin- 1-yl-methanone; v) [4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-phenyl)-4,5-dihydro-imidazol- 1-yl] piperazin-1-yl-methanone, trifluoroacetic acid salt; 5 w) [4,5-Bis-(4-chloro-phenyl)-2-(3-isopropoxy-phenyl)-4,5-dihydro-imidazol- 1 yl]-piperazin-1-yl-methanone, trifluoroacetic acid salt; x) 1- {4- [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-phenyl)-4,5-dihydro-imidazole 1-carbonyl]-piperazin- 1-yl}-ethanone; y) [4,5-Bis-(4-bromo-phenyl)-2-(2-ethoxy-phenyl)-4,5-dihydro-imidazol- 1-yl] 10 [4-(2-hydroxy-ethyl)-piperazin- 1 -yl]-methanone; z) 1- {4- [4,5-Bis-(4-bromo-phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro imidazole- 1-carbonyl] -piperazin- 1-yl}-ethanone; and aa) [4,5-Bis-(4-bromo-phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro-imidazol-1 yl]-[4-(2-hydroxy-ethyl)-piperazin-1l-yl]-methanone. 15
27. A pharmaceutical composition comprising a compound according to any one of claims 1 to 26 as an active ingredient and a pharmaceutical acceptable carrier.
28. The pharmaceutical composition according to claim 27 which is suitable for oral or parenteral administration.
29. A use of compound as defined in any one of claims 1 to 26 for the preparation of a 20 medicament.
30. The use according to claim 29 for the preparation of a medicament for the treatment or control of cell proliferative disorders.
31. The use according to claim 29 and/or 30 for the treatment or control of cancer.
32. The use according to any one of claims 29 to 31 for the treatment or control of 25 breast, colon, lung or prostate tumors. WO 03/051359 PCT/EPO2/13904 - 104
33. A method for treating a cell proliferative disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any on of claims 1 to 26.
34. The method according to claim 33 wherein the cell proliferative disorder is cancer. 5
35. The method according to claim 34 wherein the cancer is breast, colon, lung or prostate tumors.
36. The compound of any one of claims 1 to 26 for use in therapy.
37. A process for the preparation of a compound according to any one of claim 1 to 26 as depicted in scheme I to X 10
38. The invention as described herein.
Applications Claiming Priority (5)
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| US34171401P | 2001-12-18 | 2001-12-18 | |
| US60/341,714 | 2001-12-18 | ||
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| US60/390,874 | 2002-06-21 | ||
| PCT/EP2002/013904 WO2003051359A1 (en) | 2001-12-18 | 2002-12-09 | Cis-2,4,5- triphenyl-imidazolines and their use in the treatment of tumors |
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| AU2002366278B2 AU2002366278B2 (en) | 2007-07-19 |
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- 2002-12-09 AT AT02804883T patent/ATE389400T1/en active
- 2002-12-09 KR KR1020047009563A patent/KR100650966B1/en not_active IP Right Cessation
- 2002-12-09 RU RU2004122414/04A patent/RU2305095C2/en not_active IP Right Cessation
- 2002-12-09 MX MXPA04005906A patent/MXPA04005906A/en active IP Right Grant
- 2002-12-09 ES ES02804883T patent/ES2301717T3/en not_active Expired - Lifetime
- 2002-12-09 BR BR0215157-0A patent/BR0215157A/en not_active IP Right Cessation
- 2002-12-09 CN CNB028255402A patent/CN100486969C/en not_active Expired - Fee Related
- 2002-12-09 CA CA2469187A patent/CA2469187C/en not_active Expired - Fee Related
- 2002-12-09 EP EP02804883A patent/EP1458380B1/en not_active Expired - Lifetime
- 2002-12-09 PL PL02370823A patent/PL370823A1/en not_active Application Discontinuation
- 2002-12-09 KR KR1020067016636A patent/KR20060096513A/en not_active Application Discontinuation
- 2002-12-09 AU AU2002366278A patent/AU2002366278B2/en not_active Ceased
- 2002-12-11 US US10/316,695 patent/US6734302B2/en not_active Expired - Fee Related
- 2002-12-17 UY UY27585A patent/UY27585A1/en not_active Application Discontinuation
- 2002-12-17 PA PA20028561901A patent/PA8561901A1/en unknown
- 2002-12-18 TW TW091136528A patent/TW200301112A/en unknown
-
2003
- 2003-01-06 PE PE2003000024A patent/PE20030895A1/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| JP2005511766A (en) | 2005-04-28 |
| CN1606439A (en) | 2005-04-13 |
| ES2301717T3 (en) | 2008-07-01 |
| KR100650966B1 (en) | 2006-11-30 |
| CN100486969C (en) | 2009-05-13 |
| PE20030895A1 (en) | 2003-10-25 |
| TW200301112A (en) | 2003-07-01 |
| US6734302B2 (en) | 2004-05-11 |
| EP1458380B1 (en) | 2008-03-19 |
| ATE389400T1 (en) | 2008-04-15 |
| UY27585A1 (en) | 2003-06-30 |
| AU2002366278B2 (en) | 2007-07-19 |
| PA8561901A1 (en) | 2003-11-12 |
| KR20060096513A (en) | 2006-09-11 |
| BR0215157A (en) | 2004-10-19 |
| EP1458380A1 (en) | 2004-09-22 |
| RU2305095C2 (en) | 2007-08-27 |
| KR20040068277A (en) | 2004-07-30 |
| WO2003051359A1 (en) | 2003-06-26 |
| MXPA04005906A (en) | 2004-09-13 |
| DE60225719T2 (en) | 2009-04-23 |
| US20030153580A1 (en) | 2003-08-14 |
| RU2004122414A (en) | 2005-06-27 |
| CA2469187C (en) | 2012-07-17 |
| DE60225719D1 (en) | 2008-04-30 |
| PL370823A1 (en) | 2005-05-30 |
| CA2469187A1 (en) | 2003-06-26 |
| JP4477351B2 (en) | 2010-06-09 |
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Legal Events
| Date | Code | Title | Description |
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| FGA | Letters patent sealed or granted (standard patent) | ||
| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |